Larry Tremaine - Academia.edu (original) (raw)

Papers by Larry Tremaine

Abstract 10372: A Clinical Drug-Drug Interaction Study of Imb-1018972, a Novel Investigational Cardiac Mitotrope in Phase 2 Development for the Treatment of Myocardial Ischemia and Hypertrophic Cardiomyopathy

Circulation, 2021

Background: IMB-1018972 (IMB-101) is a novel mitotropic agent designed to increase myocardial met... more Background: IMB-1018972 (IMB-101) is a novel mitotropic agent designed to increase myocardial metabolic efficiency by shifting substrate utilization towards glucose through reducing fatty acid oxidation (inhibiting 3-ketoacyl CoA thiolase), thereby generating more ATP per unit of oxygen consumed. IMB-101 is hydrolyzed to IMB-1028814 (IMB-102, the active moiety) which is further metabolized with ~60% forming trimetazidine (TMZ). In vitro cytochrome P450 (CYP) studies reveal IMB-102 to be metabolized by multiple CYPs with CYP2C19 and CYP2D6 potentially comprising a major portion of its clearance and formation of TMZ. IMB-101 is under evaluation in Phase 2 studies in stable CAD, non-obstructive HCM & T2DM, indications for which patients often take multiple medications concurrently. Aim: To evaluate the drug-drug interaction (DDI) potential of IMB-101 in healthy subjects. Methods: A fixed sequence crossover study conducted in 3 parts evaluating the effect of: 1) multiple dose oral (PO) ...

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Drug metabolism and disposition: the biological fate of chemicals, Jul 1, 2018

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic... more This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species, with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a range similar to human parameters and good...

Drug metabolism and disposition: the biological fate of chemicals, 2018

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition ... more We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly ( < 0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin [area under the plasma concentration-time curve (AUC) ratio ∼21-39]. Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly ( < 0.05) impact...

Journal of pharmaceutical sciences, Jan 26, 2017

Hepatobiliary elimination can be a major clearance pathway dictating the pharmacokinetics of drug... more Hepatobiliary elimination can be a major clearance pathway dictating the pharmacokinetics of drugs. Here, we first, compared the dose eliminated in bile in preclinical species (monkey, dog and rat) to that in human; and further evaluated single-species scaling (SSS) to predict human hepatobiliary clearance. Six compounds dosed in bile-duct cannulated monkeys showed biliary excretion comparable to human; and the SSS of hepatobiliary clearance with plasma fraction unbound correction yielded reasonable predictions (within 3-fold). While dog SSS also showed reasonable predictions, rat overpredicted hepatobiliary clearance for 13 of 24 compounds. Secondly, we evaluated the translatability of in vitro sandwich-cultured human hepatocytes (SCHH) to predict human hepatobiliary clearance for 17 drugs. For drugs with no significant active uptake in SCHH studies (i.e., +/-rifamycin SV), measured intrinsic biliary clearance was directly scalable with good predictability (absolute average fold er...

The AAPS journal, May 23, 2017

The middle initial of the second author's name was missing in the original article. The second au... more The middle initial of the second author's name was missing in the original article. The second author's complete name is "Renato J. Scialis" as listed in this erratum. The original article was corrected.

The AAPS journal, May 10, 2017

Transporter-mediated hepatic uptake is proven to be the rate-determining step in the systemic cle... more Transporter-mediated hepatic uptake is proven to be the rate-determining step in the systemic clearance of several drugs. Therefore, accurate measurement of active and passive uptake clearances in vitro is critical to facilitate pharmacokinetics and drug-drug interaction predictions. Here, we evaluated the plated human hepatocytes (PHH) and studied the effect of incubation temperature and inhibitor concentration on uptake measurements, in order to reliably estimate hepatic uptake components. Uptake rates measured using PHH, at 37°C without and with rifamycin SV, were comparable with those obtained from suspension hepatocytes and sandwich-cultured hepatocytes for a set of 10-13 compounds. Apparent permeability across monolayers of low-efflux Madin-Darby canine kidney cells was measured at 4, 10, and 37°C. Of the 23 compounds evaluated, 13 compounds showed >2-fold reduction in passive permeability at 4°C compared to 37°C, inferring that low-temperature incubations may underestimate...

Metabolism and dispostion of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog

Drug Metabolism and Disposition, 1989

Journal of Pharmacological Methods, 1985

A method for the quantitative determination of organ contribution to in vivo excretory metabolism... more A method for the quantitative determination of organ contribution to in vivo excretory metabolism is described. By excretory metabolism, we mean metabolism of a compound by an organ with direct excretion. The technique separately and simultaneously quantifies clearance of circulating metabolite and clearance of circulating precursor by excretory metabolism. For xenobiotics, the method involves the simultaneous infusion of radiolabeled precursor and unlabeled metabolite. The method is dependent upon the achievement of steady-state plasma concentrations of precursor and metabolite and on the ability to accurately analyze, both chemically and radioactively, the precursor in plasma, and the metabolite in both plasma and excretory fluid. The technique is not compromised by in vivo conversion of metabolite to precursor. This method is suitable for the simultaneous quantitative determination of the contribution of several organs to the formation of any number of metabolites present in excretory fluids. The simultaneous contribution of excretory metabolism to the urinary and biliary elimination of 1-naphthol in the rat is presented.

Clinical pharmacology and therapeutics, 2005

Drug-drug interactions (DDIs) represent a serious problem in clinical practice. However, with kno... more Drug-drug interactions (DDIs) represent a serious problem in clinical practice. However, with knowledge gained over the past 15 years on the human drugmetabolizing enzymes, a better understanding of the underlying mechanisms behind many of the pharmacokinetic DDIs has been obtained. Previously, studies of DDIs for new drugs were carried out empirically or were gained through random clinical observations. In the past combinations of drugs chosen for investigation of DDIs were selected on the basis of the potential for introduction of toxicity of a drug with a narrow therapeutic index (eg, digoxin, theophylline, and warfarin) or if there was frequent coprescription with another agent for a given condition. However, with an increased understanding of drug-metabolizing enzymes and their roles in the metabolism of specific drugs, it is possible to apply a more mechanistic approach to assessing DDIs. In particular, the possibility of extrapolation of results of clinical DDI studies with 1 drug known to be cleared by a particular drug-metabolizing enzyme to other drugs that are cleared by that same enzyme is attractive.

Renal tubular excretory transport of oxalate in the chicken

The Journal of pharmacology and experimental therapeutics, 1985

By use of the Sperber in vivo chicken preparation, infusion of radiolabeled oxalic acid ([14C]oxa... more By use of the Sperber in vivo chicken preparation, infusion of radiolabeled oxalic acid ([14C]oxalate) into the renal portal circulation indicated net excretory transfer of unchanged oxalate. At infusion rates of 0.1 to 100 nmol/min, approximately 26% of the oxalate reaching the kidney was excreted directly into the urine. The excretory transport of oxalate was not altered by infusion of probenecid or terephthalic acid, at rates that blocked completely the excretory transport of simultaneously infused p-aminohippuric acid. Because probenecid and terephthalic acid are also known to inhibit uric acid excretory transport in the chicken kidney, these findings suggest that the transport system for oxalate in the chicken kidney is separate from those handling p-aminohippuric acid and uric acid. The excretory transport of oxalate was decreased by the infusion of alpha-ketoglutaric acid, suggesting that oxalate competes at least in part with other endogenous dicarboxylic acids for uptake at...

Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline

Drug metabolism and disposition: the biological fate of chemicals

In the dog, the major excretory metabolite of the antidepressant sertraline was characterized as ... more In the dog, the major excretory metabolite of the antidepressant sertraline was characterized as sertraline carbamoyl-O-glucuronide. The intact conjugate was isolated from bile by HPLC. The metabolite was labile to beta-glucuronidase and produced sertraline as the single hydrolytic product, based on HPLC and GC-MS analyses. By fast atom bombardment MS analysis, [M+H]+ and [M+Na]+ ions at m/z 526 and 548 were observed, as were the proton and sodium adducts of the aglycone (m/z 350 and 372) due to cleavage of the glycosidic bond and elimination of the glucuronic acid moiety (176 amu). The observed mass of the aglycone was 44 amu greater than sertraline, indicating that a carbamic acid of this secondary amine was conjugated with glucuronic acid. These data suggest that sertraline in solution reversibly associates with CO2 before formation of sertraline carbamoyl-O-glucuronide. This novel amine glucuronide was also identified in human plasma after the oral administration of sertraline t...

Hemoglobin Nigeria (a-81 Ser-e-Cys):A New Variant Associated With a-Thalassemia

Hematologic evaluation of a Nigerian obstetrical patient disclosed the presence of sickle-cell tr... more Hematologic evaluation of a Nigerian obstetrical patient disclosed the presence of sickle-cell trait as well as evidence of a hemoglobin a-chain abnormality. Hemoglobins containing the variant a-chain were isolated by DEAE-cellulose column chromatography. and analysis of the purified a-chain demonstrated a ser-'cys substitution at a-81 . The abnormal a-chain represented approximately 45% of the total. and hemoglobins containing this a-chain

Drug Metabolism Letters, 2007

Metabolite profiling of 100-and 1,000-fold diluted urine and plasma samples from a conventional r... more Metabolite profiling of 100-and 1,000-fold diluted urine and plasma samples from a conventional radiolabeled human ADME study is described using a highly sensitive LC-AMS technique. The concentration of radioactivity and the metabolic profiles in urine and plasma determined using this technique were similar to those employing standard off-line (i.e. LSC) or in-line (i.e.-RAM or LC-ARC dynamic-flow) radioactivity monitoring techniques. The results indicate that at a simulated ca. 100 nCi clinical dose, plasma and urine concentrations of 14 C, as well as their metabolic profiles, may be determined routinely by LC-AMS. This approach opens the possibility of using LC-AMS for both the highthroughput quantitation of biological samples and the generation of high-resolution chromatographic profiles of complex mixtures at a lower cost than current AMS analyses that require the conversion of sample carbon to graphite, a laborious and time consuming process.

Drug Metabolism and Disposition, 2011

The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With... more The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drugs metabolic clearance,

Drug Metabolism and Disposition, 2012

A novel relay method has been developed using cryopreserved human hepatocytes to measure intrinsi... more A novel relay method has been developed using cryopreserved human hepatocytes to measure intrinsic clearance of low-clearance compounds. The relay method involved transferring the supernatant from hepatocyte incubations to freshly thawed hepatocytes at the end of the 4-h incubation to prolong the exposure time to active enzymes in hepatocytes. An accumulative incubation time of 20 h or longer in hepatoctyes can be achieved using the method. The relay method was validated using seven commercial drugs (diazepam, disopyramide, theophylline, timolol, tolbutamide, S-warfarin, and zolmitriptan) that were metabolized by various cytochrome P450s with low human in vivo intrinsic clearance at approximately 2 to 15 ml ⅐ min ؊1 ⅐ kg ؊1. The results showed that the relay method produced excellent predictions of human in vivo clearance. The difference between in vitro and in vivo intrinsic clearance was within 2-fold for most compounds, which is similar to the standard prediction accuracy for moderate to high clearance compounds using hepatocytes. The relay method is a straightforward, relatively low cost, and easy-to-use new tool to address the challenges of low clearance in drug discovery and development.

Biochemical Pharmacology, 1984

The simultaneous in vivo renal sulfate and glucuronide conjugations of 1-naphthol (1-N) and p-nit... more The simultaneous in vivo renal sulfate and glucuronide conjugations of 1-naphthol (1-N) and p-nitrophenol (PNP) were determined in the rat. In mammals, 1-N and PNP are excreted almost entirely in the urine. mainly as the glucuronide and sulfate conjugates. In male Sprague-Dawiey rats, greater than 98% of the infused ['"CJl-N (l.Opmole~min-I kg-') or [14C]PNP (2.0 pmoles min-' kg-!) recovered in urine was identified as the sulfate and glucuronide conjugates. Renal metabolism accounted for a minimum of 20% of the endogenously formed conjugates of either substrate excreted in the urine. The rat kidney formed the glucuronide and sulfate conjugates of PNP at equal rates, whereas the glucuronide : sulfate conjugate ratio for renally formed 1-N conjugates was 3 : 1. When the conjugates of either 1-N or PNP were infused systemically, in uivo hydrolysis contributed significantly to the amount of circulating parent phenol.

Journal of Pharmacology and Experimental Therapeutics, 2005

The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI)... more The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI) was examined for over 40 drugs using seven human P450 selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C max , estimated hepatic inlet C max , fraction unbound, and fraction of the probe drug cleared by the inhibited enzyme) to predict increases in exposure to probe drugs, and the predictions were compared to in vivo DDI gathered from clinical studies reported in the scientific literature. For drugs that had been tested as precipitants of drug interactions for more than one P450 in vivo, the order of inhibitory potencies in vitro generally aligned with the magnitude of the in vivo interactions. With the exception of many drugs known to be mechanism-based inactivators, use of in vitro IC 50 , fraction of the affected drug metabolized by the target enzyme (f m(CYP)), and an estimate of free hepatic inlet C max was generally successful in identifying those drugs that cause at least a 2-fold increase in the exposure to P450 marker substrate drugs. For CYP3A, incorporation of inhibition of both hepatic and intestinal metabolism was needed for prediction of DDI. Many CYP3A inhibitors showed a different inhibitory potency for three different CYP3A marker activities, however, these differences generally did not alter the conclusions regarding whether a drug would cause a CYP3A DDI in vivo. Overall, these findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI.

In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptide... more In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10 and 30 mg/kg) that generated plasma free C max values (0.06, 0.66, 2.57 and 7.79 µM, respectively) that covered the reported in vitro IC 50 s for OATP1B1 and OATP1B3 (≤ 1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (intravenous 2 H 4-pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled also and it was determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ≥50-fold increase in plasma AUC) was observed for the sulfates of five BAs (glycodeoxycholate [GDCA-S], glycochenodeoxycholate [GCDCA-S], taurochenodeoxycholate, deoxycholate [DCA-S], and taurodeoxycholate [TDCA-S]). In vitro, RIF (≤ 100 μM) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥ 70%) by RIF (5 μM); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). It is concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs. Exploration of their utility as circulating human OATP biomarkers is warranted.

Phase 1 Safety and Tolerability Study of IMB-1018972, a Novel Oral Modulator of Myocardial Substrate Utilization Designed to Improve Cardiac Metabolic Efficiency and Bioenergetics

Journal of the American College of Cardiology, 2021