Handan He - Academia.edu (original) (raw)
Papers by Handan He
Drug metabolism and disposition: the biological fate of chemicals, Jan 26, 2016
KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malari... more KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. Following oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤ 11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥ 93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Amongst the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1, 2-acyl shift to form a ring expansion me...
Integrative Approaches in Drug Discovery and Development, 2014
Journal of pharmaceutical sciences, Jan 17, 2015
Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro... more Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka ) from preclinical species. Key PK parameters evaluated were the...
Encyclopedia of Drug Metabolism and Interactions, 2011
ABSTRACT Mass balance studies play an important role in the development of new drugs. These studi... more ABSTRACT Mass balance studies play an important role in the development of new drugs. These studies give in-depth understanding of absorption, bioavailability, and routes (renal, biliary, hepatic, or gastrointestinal) and extent of excretion, metabolite profiling, metabolic pathways, and clearance mechanisms of a drug. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive absorption, distribution, ...
European Journal of Pharmaceutical Sciences, 2014
Journal of Pharmaceutical Sciences, 2005
Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosa... more Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosage forms based on in vitro studies are important in order to minimize costly animal and human experiments during drug development. Because of issues related to poor solubility and low permeability of newer drug candidates, there has in recent years been a special focus on in vitro-in vivo correlation (IV-IVC) of drug products, particularly those used orally. Various physicochemical, biopharmaceutical, and physiological factors that need to be considered in successful IV-IVC of immediate-release oral dosage forms are reviewed in this article. The physicochemical factors include drug solubility in water and physiologically relevant aqueous media, pK(a) and drug ionization characteristics, salt formation, drug diffusion-layer pH, particle size, polymorphism of drug substance, and so forth. The biopharmaceutical factors that need to be considered include effects of drug ionization, partition coefficient, polar surface area, etc., on drug permeability, and some of the physiological factors are gastrointestinal (GI) content, GI pH, GI transit time, etc. Various in silico, in vitro, and in vivo methods of estimating drug permeability and absorption are discussed. Additionally, how IV-IVC may be applied to immediate-release oral dosage form design are presented.
Journal of Pharmaceutical Sciences, 2011
Abbreviations used: PK, pharmacokinetics; IVIVE, in vitro-in vivo extrapolation; log P, log octan... more Abbreviations used: PK, pharmacokinetics; IVIVE, in vitro-in vivo extrapolation; log P, log octanol:water partition coefficient; MW, molecular weight; fu p , fraction unbound in plasma; fu inc , fraction unbound in incubation media; CL int , intrinsic clearance; CL, intravenous clearance; Q liver , hepartic blood flow rate; MA, multiexponential allometry; SA, simple allometry; SS, singlespecies-based allometry/proportionality equation; TS, two-speciesbased allometry; SSS, single-species-based allometry using a fixed exponent; BW, body weight; PBSF, physiologically based scaling factor; QSAR, quantitative structure-activity relationship; FCIM, fu-corrected intercept method; ROE, rule of exponent; RSF, rat scal-ABSTRACT: The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUC p.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUC p.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.
Journal of Pharmaceutical Sciences, 2009
The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as... more The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 mg/mL at pH 1-8 and 258C) was dissolved in a melt of the mixture at 65-708C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 558C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-608C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.
Journal of Medicinal Chemistry, 2010
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series o... more Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Drug Metabolism and Disposition, 2009
The pharmacokinetics, absorption, metabolism and excretion of vildaglitin, a potent and orally ac... more The pharmacokinetics, absorption, metabolism and excretion of vildaglitin, a potent and orally active inhibitor of dipeptidylpeptidase 4 (DPP-4) were evaluated in male rats and dogs. Vildaglitin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h (82% of AUC) and 8.8 h in the rat, and 0.05 h and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution (V ss ) was 1.6 and 8.6 l/kg in dogs and rats respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) when compared to their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog) and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs, as 18.9-21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose).
Drug Metabolism and Disposition, 2009
The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(... more The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [(14)C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
Cancer Chemotherapy and Pharmacology, 2012
Purpose Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated fo... more Purpose Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated for cancer treatment. A novel physiologically based pharmacokinetics (PBPK) model was developed based on nonclinical data to predict the disposition of patupilone in cancer patients.
Biopharmaceutics & Drug Disposition, 2012
Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatme... more Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosomepositive (Ph+) chronic myeloid leukemia (CML). Nilotinib preclinical data and its use for practical predictions of systemic exposure profiles and oral absorption are described. The systemic clearance (CL) of nilotinib was relatively low in rodents with a value of less than 25% of hepatic blood flow (Q H ), while it was moderate in monkeys and dogs (CL /Q H = 32-35%). The steady state volume of distribution (V ss ) ranged from 0.55 to 3.9 l/kg across the species tested. The maximum concentration (C max ) of nilotinib occurred at 0.5-4 h and the bioavailability was moderate (17-44%). The plasma protein binding was high (> 97.5%) in preclinical species and humans. The human CL (~0.1 l/h/kg) and V ss (~2.0 l/kg) were best predicted by the rat-dog-human proportionality method and allometric scaling method, respectively. The human intravenous pharmacokinetic profile was projected by the Wajima 'C ss -MRT' method. The predicted micro-constants from human intravenous profiles were incorporated into the advanced compartmental absorption and transit model within the GastroPlus program to simulate the oral concentration-time curves in humans. Overall, the simulated oral human pharmacokinetic profiles showed good agreement with observed clinical data, and the model predicted that the C max , AUC, t 1/2 , V z /F and CL/F values were within 1.3-fold of the observed values. The absolute oral bioavailability of nilotinib in healthy humans was predicted to be low (< 25%). Copyright
Biomedical Chromatography, 2007
A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the deter... more A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of N-methyl-4-isoleucine-cyclosporin (NIM811) was developed and validated over the concentration range 1-2500 ng/mL in human whole blood using a 0.05 mL sample volume. NIM811 and the internal standard, d(12)-cyclosporin A (d(12)-CsA), were extracted from blood using MTBE via liquid-liquid extraction. After evaporation of the organic solvent and reconstitution, a 10 microL aliquot of the resulting extract was injected onto the LC-MS/MS system. Chromatographic separation of NIM811 and internal standard was performed using a Waters Symmetry RP-8 (50 x 4.6 mm, 3 microm particle size) column. The mobile phase consists of 10 mm ammonium acetate in water (A) and acetonitrile (B), with 45% B from 0 to 0.2 min, 45 to 85% B from 0.2 to 0.8 min and 85% B from 0.8 to 2.2 min. The total run time was 3.5 min with a flow rate of 0.8 mL/min. The method was validated for sensitivity, linearity, reproducibility, stability, dilution integrity and recovery. The precision and accuracy of quality control samples at low (2.00 ng/mL), medium (20.0 and 400 ng/mL) and high (2000 ng/mL) concentrations were in the range 1.1-4.3% relative standard deviation (RSD) and -2.5-10.0% (bias), respectively, from three validation runs. The method has been used to measure the exposure of NIM811 in human subjects.
Antiviral Research, 2010
Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus pose... more Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections. antiviral therapy ͉ flavivirus ͉ viral replication T he family Flaviviridae includes 3 genera: Flaviviruses, Pestiviruses, and Hepacivirus. Many members from the genus Flavivirus are arthropod-borne and cause significant human diseases, such as the 4 serotypes of dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) (1). Human vaccines are currently available only for YFV, JEV, and TBEV. Development of a vaccine for DENV has been challenging, principally because of the need to immunize and induce long-lasting protection against all 4 serotypes of DENV simultaneously; an incompletely immunized individual may be sensitized to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), either of which is a life-threatening disease (2). These complications have underscored the importance for development of an effective therapy for DENV and other flavivirus infections.
Antimicrobial Agents and Chemotherapy, 2010
We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydr... more We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC 50 ) and cytotoxic concentration (CC 50 ) values of 0.7 M and >100 M, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14 C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.
AAPS PharmSciTech, 2014
Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug de... more Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug development, hereby we developed a PBPK model to systematically investigate the underlying mechanisms of the observed positive food effect of compound X (cpd X) and to strategically explore the feasible approaches to mitigate the food effect. Cpd X is a weak base with pH-dependent solubility; the compound displays significant and dose-dependent food effect in humans, leading to a nonadherence of drug administration. A GastroPlus Opt logD Model was selected for pharmacokinetic simulation under both fasted and fed conditions, where the biopharmaceutic parameters (e.g., solubility and permeability) for cpd X were determined in vitro, and human pharmacokinetic disposition properties were predicted from preclinical data and then optimized with clinical pharmacokinetic data. A parameter sensitivity analysis was performed to evaluate the effect of particle size on the cpd X absorption. A PBPK model was successfully developed for cpd X; its pharmacokinetic parameters (e.g., C max, AUCinf, and t max) predicted at different oral doses were within ±25% of the observed mean values. The in vivo solubility (in duodenum) and mean precipitation time under fed conditions were estimated to be 7.4- and 3.4-fold higher than those under fasted conditions, respectively. The PBPK modeling analysis provided a reasonable explanation for the underlying mechanism for the observed positive food effect of the cpd X in humans. Oral absorption of the cpd X can be increased by reducing the particle size (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100 nm) of an active pharmaceutical ingredient under fasted conditions and therefore, reduce the cpd X food effect correspondingly.
AAPS PharmSciTech, 2013
Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the pe... more Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the performance of orally administrated drugs. Here, we described multiple in silico/in vitro/in vivo tools to support formulation development toward mitigating the positive food effect of NVS123, a weak base with a pH-dependent and limited solubility. Administered orally with high-fat meal, NVS123 formulated as dry filled capsules displayed a positive food effects in humans. Three alternative formulations were developed and assessed in in vitro and in vivo preclinical and/or clinical studies. By integrating preclinical in vitro and in vivo data, the PBPK model successfully estimated the magnitude of food effects and the predicted values were within ± 30% of the observed results. A model-guided parameter sensitivity analysis illustrated that enhanced solubility and longer precipitation times under fed condition were the main reason for enhanced NVS123&amp;amp;amp;amp;amp;amp;amp;#39;s exposure in presence of food. Eventually, exposure after an amorphous formulation was found to be not significantly altered because of remarkably enhanced intestinal solubility and reduced precipitation. Gastroplus population simulations also suggested that the amorphous formulation is promising in mitigating a clinically significant food effect. Overall, these efforts supported the rationale of clinical investigation of the new formulation, and more importantly, highlighted a practical application of PBPK modeling solving issues of undesirable food effects in weakly basic compounds based on preclinical in vitro/in vivo data.
The AAPS Journal, 2013
During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential sy... more During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential systemic exposure changes is highly desirable. Physiologically based pharmacokinetics (PBPK) models have recently been used to influence clinical trial design or to facilitate regulatory interactions. Ideally, whole-body PBPK models can be used to predict a drug's systemic exposure in pregnant women based on major physiological changes which can impact drug clearance (i.e., in the kidney and liver) and distribution (i.e., adipose and fetoplacental unit). We described a simple and readily implementable multitissue/organ whole-body PBPK model with key pregnancy-related physiological parameters to characterize the PK of reference drugs (metformin, digoxin, midazolam, and emtricitabine) in pregnant women compared with the PK in nonpregnant or postpartum (PP) women. Physiological data related to changes in maternal body weight, tissue volume, cardiac output, renal function, blood flows, and cytochrome P450 activity were collected from the literature and incorporated into the structural PBPK model that describes HV or PP women PK data. Subsequently, the changes in exposure (area under the curve (AUC) and maximum concentration (C max )) in pregnant women were simulated. Model-simulated PK profiles were overall in agreement with observed data. The prediction fold error for C max and AUC ratio (pregnant vs. nonpregnant) was less than 1.3-fold, indicating that the pregnant PBPK model is useful. The utilization of this simplified model in drug development may aid in designing clinical studies to identify potential exposure changes in pregnant women a priori for compounds which are mainly eliminated renally or metabolized by CYP3A4.
The AAPS Journal, 2009
Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical i... more Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and &amp;amp;amp;quot;developable&amp;amp;amp;quot; dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the &amp;amp;amp;quot;anticipation&amp;amp;amp;quot; of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for &amp;amp;amp;quot;AHD&amp;amp;amp;quot; demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via &amp;amp;amp;quot;reverse pharmacology strategies&amp;amp;amp;quot; that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.
Drug metabolism and disposition: the biological fate of chemicals, Jan 26, 2016
KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malari... more KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. Following oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤ 11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥ 93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Amongst the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1, 2-acyl shift to form a ring expansion me...
Integrative Approaches in Drug Discovery and Development, 2014
Journal of pharmaceutical sciences, Jan 17, 2015
Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro... more Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka ) from preclinical species. Key PK parameters evaluated were the...
Encyclopedia of Drug Metabolism and Interactions, 2011
ABSTRACT Mass balance studies play an important role in the development of new drugs. These studi... more ABSTRACT Mass balance studies play an important role in the development of new drugs. These studies give in-depth understanding of absorption, bioavailability, and routes (renal, biliary, hepatic, or gastrointestinal) and extent of excretion, metabolite profiling, metabolic pathways, and clearance mechanisms of a drug. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive absorption, distribution, ...
European Journal of Pharmaceutical Sciences, 2014
Journal of Pharmaceutical Sciences, 2005
Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosa... more Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosage forms based on in vitro studies are important in order to minimize costly animal and human experiments during drug development. Because of issues related to poor solubility and low permeability of newer drug candidates, there has in recent years been a special focus on in vitro-in vivo correlation (IV-IVC) of drug products, particularly those used orally. Various physicochemical, biopharmaceutical, and physiological factors that need to be considered in successful IV-IVC of immediate-release oral dosage forms are reviewed in this article. The physicochemical factors include drug solubility in water and physiologically relevant aqueous media, pK(a) and drug ionization characteristics, salt formation, drug diffusion-layer pH, particle size, polymorphism of drug substance, and so forth. The biopharmaceutical factors that need to be considered include effects of drug ionization, partition coefficient, polar surface area, etc., on drug permeability, and some of the physiological factors are gastrointestinal (GI) content, GI pH, GI transit time, etc. Various in silico, in vitro, and in vivo methods of estimating drug permeability and absorption are discussed. Additionally, how IV-IVC may be applied to immediate-release oral dosage form design are presented.
Journal of Pharmaceutical Sciences, 2011
Abbreviations used: PK, pharmacokinetics; IVIVE, in vitro-in vivo extrapolation; log P, log octan... more Abbreviations used: PK, pharmacokinetics; IVIVE, in vitro-in vivo extrapolation; log P, log octanol:water partition coefficient; MW, molecular weight; fu p , fraction unbound in plasma; fu inc , fraction unbound in incubation media; CL int , intrinsic clearance; CL, intravenous clearance; Q liver , hepartic blood flow rate; MA, multiexponential allometry; SA, simple allometry; SS, singlespecies-based allometry/proportionality equation; TS, two-speciesbased allometry; SSS, single-species-based allometry using a fixed exponent; BW, body weight; PBSF, physiologically based scaling factor; QSAR, quantitative structure-activity relationship; FCIM, fu-corrected intercept method; ROE, rule of exponent; RSF, rat scal-ABSTRACT: The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUC p.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUC p.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.
Journal of Pharmaceutical Sciences, 2009
The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as... more The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 mg/mL at pH 1-8 and 258C) was dissolved in a melt of the mixture at 65-708C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 558C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-608C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.
Journal of Medicinal Chemistry, 2010
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series o... more Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Drug Metabolism and Disposition, 2009
The pharmacokinetics, absorption, metabolism and excretion of vildaglitin, a potent and orally ac... more The pharmacokinetics, absorption, metabolism and excretion of vildaglitin, a potent and orally active inhibitor of dipeptidylpeptidase 4 (DPP-4) were evaluated in male rats and dogs. Vildaglitin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h (82% of AUC) and 8.8 h in the rat, and 0.05 h and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution (V ss ) was 1.6 and 8.6 l/kg in dogs and rats respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) when compared to their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog) and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs, as 18.9-21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose).
Drug Metabolism and Disposition, 2009
The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(... more The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [(14)C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
Cancer Chemotherapy and Pharmacology, 2012
Purpose Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated fo... more Purpose Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated for cancer treatment. A novel physiologically based pharmacokinetics (PBPK) model was developed based on nonclinical data to predict the disposition of patupilone in cancer patients.
Biopharmaceutics & Drug Disposition, 2012
Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatme... more Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosomepositive (Ph+) chronic myeloid leukemia (CML). Nilotinib preclinical data and its use for practical predictions of systemic exposure profiles and oral absorption are described. The systemic clearance (CL) of nilotinib was relatively low in rodents with a value of less than 25% of hepatic blood flow (Q H ), while it was moderate in monkeys and dogs (CL /Q H = 32-35%). The steady state volume of distribution (V ss ) ranged from 0.55 to 3.9 l/kg across the species tested. The maximum concentration (C max ) of nilotinib occurred at 0.5-4 h and the bioavailability was moderate (17-44%). The plasma protein binding was high (> 97.5%) in preclinical species and humans. The human CL (~0.1 l/h/kg) and V ss (~2.0 l/kg) were best predicted by the rat-dog-human proportionality method and allometric scaling method, respectively. The human intravenous pharmacokinetic profile was projected by the Wajima 'C ss -MRT' method. The predicted micro-constants from human intravenous profiles were incorporated into the advanced compartmental absorption and transit model within the GastroPlus program to simulate the oral concentration-time curves in humans. Overall, the simulated oral human pharmacokinetic profiles showed good agreement with observed clinical data, and the model predicted that the C max , AUC, t 1/2 , V z /F and CL/F values were within 1.3-fold of the observed values. The absolute oral bioavailability of nilotinib in healthy humans was predicted to be low (< 25%). Copyright
Biomedical Chromatography, 2007
A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the deter... more A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of N-methyl-4-isoleucine-cyclosporin (NIM811) was developed and validated over the concentration range 1-2500 ng/mL in human whole blood using a 0.05 mL sample volume. NIM811 and the internal standard, d(12)-cyclosporin A (d(12)-CsA), were extracted from blood using MTBE via liquid-liquid extraction. After evaporation of the organic solvent and reconstitution, a 10 microL aliquot of the resulting extract was injected onto the LC-MS/MS system. Chromatographic separation of NIM811 and internal standard was performed using a Waters Symmetry RP-8 (50 x 4.6 mm, 3 microm particle size) column. The mobile phase consists of 10 mm ammonium acetate in water (A) and acetonitrile (B), with 45% B from 0 to 0.2 min, 45 to 85% B from 0.2 to 0.8 min and 85% B from 0.8 to 2.2 min. The total run time was 3.5 min with a flow rate of 0.8 mL/min. The method was validated for sensitivity, linearity, reproducibility, stability, dilution integrity and recovery. The precision and accuracy of quality control samples at low (2.00 ng/mL), medium (20.0 and 400 ng/mL) and high (2000 ng/mL) concentrations were in the range 1.1-4.3% relative standard deviation (RSD) and -2.5-10.0% (bias), respectively, from three validation runs. The method has been used to measure the exposure of NIM811 in human subjects.
Antiviral Research, 2010
Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus pose... more Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections. antiviral therapy ͉ flavivirus ͉ viral replication T he family Flaviviridae includes 3 genera: Flaviviruses, Pestiviruses, and Hepacivirus. Many members from the genus Flavivirus are arthropod-borne and cause significant human diseases, such as the 4 serotypes of dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) (1). Human vaccines are currently available only for YFV, JEV, and TBEV. Development of a vaccine for DENV has been challenging, principally because of the need to immunize and induce long-lasting protection against all 4 serotypes of DENV simultaneously; an incompletely immunized individual may be sensitized to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), either of which is a life-threatening disease (2). These complications have underscored the importance for development of an effective therapy for DENV and other flavivirus infections.
Antimicrobial Agents and Chemotherapy, 2010
We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydr... more We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC 50 ) and cytotoxic concentration (CC 50 ) values of 0.7 M and >100 M, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14 C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.
AAPS PharmSciTech, 2014
Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug de... more Physiologically based pharmacokinetic (PBPK) modeling has been broadly used to facilitate drug development, hereby we developed a PBPK model to systematically investigate the underlying mechanisms of the observed positive food effect of compound X (cpd X) and to strategically explore the feasible approaches to mitigate the food effect. Cpd X is a weak base with pH-dependent solubility; the compound displays significant and dose-dependent food effect in humans, leading to a nonadherence of drug administration. A GastroPlus Opt logD Model was selected for pharmacokinetic simulation under both fasted and fed conditions, where the biopharmaceutic parameters (e.g., solubility and permeability) for cpd X were determined in vitro, and human pharmacokinetic disposition properties were predicted from preclinical data and then optimized with clinical pharmacokinetic data. A parameter sensitivity analysis was performed to evaluate the effect of particle size on the cpd X absorption. A PBPK model was successfully developed for cpd X; its pharmacokinetic parameters (e.g., C max, AUCinf, and t max) predicted at different oral doses were within ±25% of the observed mean values. The in vivo solubility (in duodenum) and mean precipitation time under fed conditions were estimated to be 7.4- and 3.4-fold higher than those under fasted conditions, respectively. The PBPK modeling analysis provided a reasonable explanation for the underlying mechanism for the observed positive food effect of the cpd X in humans. Oral absorption of the cpd X can be increased by reducing the particle size (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100 nm) of an active pharmaceutical ingredient under fasted conditions and therefore, reduce the cpd X food effect correspondingly.
AAPS PharmSciTech, 2013
Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the pe... more Physiologically based pharmacokinetic (PBPK) modeling has become a useful tool to estimate the performance of orally administrated drugs. Here, we described multiple in silico/in vitro/in vivo tools to support formulation development toward mitigating the positive food effect of NVS123, a weak base with a pH-dependent and limited solubility. Administered orally with high-fat meal, NVS123 formulated as dry filled capsules displayed a positive food effects in humans. Three alternative formulations were developed and assessed in in vitro and in vivo preclinical and/or clinical studies. By integrating preclinical in vitro and in vivo data, the PBPK model successfully estimated the magnitude of food effects and the predicted values were within ± 30% of the observed results. A model-guided parameter sensitivity analysis illustrated that enhanced solubility and longer precipitation times under fed condition were the main reason for enhanced NVS123&amp;amp;amp;amp;amp;amp;amp;#39;s exposure in presence of food. Eventually, exposure after an amorphous formulation was found to be not significantly altered because of remarkably enhanced intestinal solubility and reduced precipitation. Gastroplus population simulations also suggested that the amorphous formulation is promising in mitigating a clinically significant food effect. Overall, these efforts supported the rationale of clinical investigation of the new formulation, and more importantly, highlighted a practical application of PBPK modeling solving issues of undesirable food effects in weakly basic compounds based on preclinical in vitro/in vivo data.
The AAPS Journal, 2013
During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential sy... more During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential systemic exposure changes is highly desirable. Physiologically based pharmacokinetics (PBPK) models have recently been used to influence clinical trial design or to facilitate regulatory interactions. Ideally, whole-body PBPK models can be used to predict a drug's systemic exposure in pregnant women based on major physiological changes which can impact drug clearance (i.e., in the kidney and liver) and distribution (i.e., adipose and fetoplacental unit). We described a simple and readily implementable multitissue/organ whole-body PBPK model with key pregnancy-related physiological parameters to characterize the PK of reference drugs (metformin, digoxin, midazolam, and emtricitabine) in pregnant women compared with the PK in nonpregnant or postpartum (PP) women. Physiological data related to changes in maternal body weight, tissue volume, cardiac output, renal function, blood flows, and cytochrome P450 activity were collected from the literature and incorporated into the structural PBPK model that describes HV or PP women PK data. Subsequently, the changes in exposure (area under the curve (AUC) and maximum concentration (C max )) in pregnant women were simulated. Model-simulated PK profiles were overall in agreement with observed data. The prediction fold error for C max and AUC ratio (pregnant vs. nonpregnant) was less than 1.3-fold, indicating that the pregnant PBPK model is useful. The utilization of this simplified model in drug development may aid in designing clinical studies to identify potential exposure changes in pregnant women a priori for compounds which are mainly eliminated renally or metabolized by CYP3A4.
The AAPS Journal, 2009
Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical i... more Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and &amp;amp;amp;quot;developable&amp;amp;amp;quot; dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the &amp;amp;amp;quot;anticipation&amp;amp;amp;quot; of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for &amp;amp;amp;quot;AHD&amp;amp;amp;quot; demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via &amp;amp;amp;quot;reverse pharmacology strategies&amp;amp;amp;quot; that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.