Jean-Francois Marier - Academia.edu (original) (raw)

Papers by Jean-Francois Marier

British Journal of Clinical Pharmacology, Mar 1, 2023

AimsTrilaciclib is a first‐in‐class, intravenous cyclin‐dependent kinase 4/6 inhibitor that provi... more AimsTrilaciclib is a first‐in‐class, intravenous cyclin‐dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy‐induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure–response relationships in extensive‐stage small cell lung cancer (ES‐SCLC) and triple‐negative breast cancer (TNBC) trials.MethodsPopulation PK analysis was performed using data from healthy volunteers (n = 72), patients with ES‐SCLC (n = 111) and patients with TNBC (n = 14). Exposure–response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time‐to‐event endpoints, respectively.ResultsTrilaciclib PK was described by a three‐compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure–response analyses, lower and higher exposures of trilaciclib at clinical doses (200–280 mg/m2) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions.ConclusionNo dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2).

Pharmaceutical Sciences Encyclopedia, Mar 15, 2010

Considering the complexity involved in drug discovery and development processes, it is imperative... more Considering the complexity involved in drug discovery and development processes, it is imperative that companies adopt strategies and technologies that will facilitate the identification and development of new therapies. Appropriate PK/PD modeling of biomarkers and surrogate endpoints facilitate proof-of-concept demonstrations for target modulation and enhance the rational selection of an optimal drug dose and schedule. This article focuses on the PK/PD correlation assessment of a drug and a biomarker, and the use of PK/PD modeling and simulation to optimize drug development and decision making. Keywords: correlation assessment; biomarker; drugs; PK/PD modeling

$Research paper thumbnail of CPX-351 Exposure-Response Analyses for Efficacy and Safety in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)$

Blood, Nov 5, 2020

CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal enca... more CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a synergistic 1:5 molar ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Separate studies at Cincinnati Children's Hospital (CCH) and by the Children's Oncology Group (COG) evaluated the efficacy and safety of CPX-351 in pediatric patients (pts). CPX-351 was administered by IV infusion on Days 1, 3, and 5 for the first induction only. The CCH study included 2 dose levels, 100 and 134 units/m2, with 100 units/m2 identified as the recommended phase 2 dose (RP2D); pts with multiple relapsed or refractory AML were included in the exposure-response (E-R) analyses. The COG study established an RP2D of 135 units/m2; the majority of pts in the E-R analyses had first-relapsed AML. E-R analyses were conducted to evaluate the relationship between plasma exposures to CPX-351 and efficacy or safety endpoints. Plasma PK parameters of cytarabine and daunorubicin, including area under the curve up to 48 h post dose on Day 5 Cycle 1 (AUC48), maximum concentration on Day 5 Cycle 1 (Cmax), and concentration at 48 h post dose on Day 5 Cycle 1 (C48), were derived from a previously developed population PK model for pediatric and adult pts. The efficacy endpoints were complete remission (CR), CR+CRp (partial platelet count recovery), or CR+CRp+CRi (incomplete hematologic recovery). Age, sex, bone marrow blast, white blood cell, and platelet counts at baseline were included in the covariate analysis. The safety endpoints included grade ≥3 TEAEs. From the studies, both pediatric and adult pts were included in the E-R analyses for efficacy. Overall, the E-R efficacy population included 43 (53%) pediatric pts (1-17 y) and 38 (47%) adults (≥18 y); the majority were male (57%) and of white origin (63%). Of the 81 pts included in the analysis, 28 (31%), 16 (25%), and 1 (2%) pt achieved CR, CRp, and CRi, respectively; 39 (48%) pts had progressive disease or no response. Various models were used to describe the relationship between probability of response (CR, CRi, or CRp) and exposure parameters (AUC48, Cmax, and C48). C48 of cytarabine was associated with the best statistical goodness-of-fit in the logistic regression model. The effect of cytarabine C48 on the probability of response was statistically significant (P = 0.0144; odds ratio = 1.057). These results suggest the odds of response increased by ~6% for each 1-unit increment of cytarabine C48 (ie, 1 μg/mL). The estimated probability of response was separated into exposure quartiles: 33% for Q1, 49% for Q2, 59% for Q3, and 83% for Q4. The cytarabine C48 was mainly observed in Q1 and Q2 for the 100 units/m2 dose and in Q3 and Q4 for the 134-135 units/m2 doses. In a covariate analysis, none of the covariates tested explained the variability in response. AUC48 of cytarabine and daunorubicin and C48 of daunorubicin were also significantly correlated with probability of response to CPX-351. This was expected, as the PK of daunorubicin and cytarabine are highly correlated when administered as CPX-351. Logistic models were also developed to describe the relationship between probability of response and exposure parameters. Similarly, cytarabine C48 was a significant predictor of the probability of CR or CRi. However, no logistic models were found to describe the relationship of probability of CR+CRp (or CR only) and exposure parameters. Although pt populations of the CCH and COG studies were different, a similar correlation was shown for exposures and efficacy in the CCH study, where higher exposures were associated with higher response rates. Grade ≥3 TEAEs observed in pediatric pts were separated into exposure quartiles for Cmax of cytarabine or daunorubicin. The probabilities of grade ≥3 TEAEs for quartiles of cytarabine Cmax were 77% for Q1, 85% for Q2, 85% for Q3, and 71% for Q4. Similar results were observed with daunorubicin. In these post hoc E-R analyses, higher CPX-351 doses were associated with higher plasma exposures, which led to a higher probability of response (CR+CRp+CRi) in pediatric pts with relapsed or refractory AML. There was no correlation of plasma exposures to grade ≥3 TEAEs. These analyses should be interpreted with caution due to the small sample size; however, they support use of the higher dose of 135 units/m2. Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Absalon:Jazz Pharmaceuticals: Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Yes, in these studies, CPX-351 was evaluated in pediatric AML

Clinical pharmacology in drug development, Feb 10, 2014

Dutogliptin is a selective dipeptidyl peptidase‐4 inhibitor shown to be efficacious and safe in p... more Dutogliptin is a selective dipeptidyl peptidase‐4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug–drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non‐linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two‐compartment model with a first‐order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half‐life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug–drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.

Therapeutic Innovation & Regulatory Science, Sep 1, 2013

Trial simulations have emerged as a promising tool to optimize pediatric drug development program... more Trial simulations have emerged as a promising tool to optimize pediatric drug development programs. As the current FDA legislation on pediatric drugs and devices was updated to mirror the EMA legislation, pediatric programs must be developed with global strategies that support a Pediatric Investigation Plan (PIP) for the EMA and a Pediatric Study Plan (PSP) for the FDA. A pharmacometrics framework is proposed to support global regulatory strategies for pediatric drug development programs. The framework describes specific trigger points and opportunities for applying modeling and simulation techniques to design the PIP and PSP and ultimately optimize pediatric drug development programs. The development of pediatric protocols by simulations and execution plans is deemed critical in defining expectations and ensuring the future success of these global programs. This can lead to clinical trial designs that are more efficient, less prone to failure, and ultimately, less costly.

Antimicrobial Agents and Chemotherapy, Jun 1, 2011

TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this ... more TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (E max) and 50% inhibitory concentrations (IC 50). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an E max of ؊1.43 log 10 copies/ml and IC 50 of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.

The Journal of Clinical Pharmacology, Oct 26, 2015

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated s... more X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate, and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05 to 0.6 mg/kg) and a subsequent 12-month titration period (0.1 to 1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a one-compartmental model with first-order absorption and elimination at doses ≥ 0.1 mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing, and progressively increased following each of the initial 4 doses with comparable peak values attained following the 6th through 10th doses with a slight decrease thereafter. A PK-PD model with a maximum effect (Emax ) and a time-varying concentration to reach 50% of Emax (EC50 ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50 was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively. This article is protected by copyright. All rights reserved.

Investigational New Drugs, Mar 16, 2017

Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer... more Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/ carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m 2 and subsequent doses 250 mg/m 2 , weekly; carboplatin, 6 mg/mL/min AUC Key message This randomized Phase II study (N = 90) evaluated the addition of BTH1677, a novel pathogen-associated molecular pattern (PAMP) immunotherapy, to anti-tumor antibody and chemotherapy (cetuximab/carboplatin/paclitaxel) in previously untreated advancedstage non-small cell lung cancer (NSCLC) patients. Addition of BTH1677 improved overall response rates compared to antibody and chemotherapy alone.

The Journal of Clinical Pharmacology, Nov 1, 2008

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treat... more Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a doubleblinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

Journal of Pharmaceutical and Biomedical Analysis, Sep 1, 2005

A rapid, selective and sensitive method was developed for the determination of propofol concentra... more A rapid, selective and sensitive method was developed for the determination of propofol concentration using an off-line dansyl chloride derivatization step to enhance signal intensity. The method consisted of a protein precipitation extraction followed by derivatization with dansyl chloride and analysis by liquid chromatography ionspray tandem mass spectrometry (LC-ESI/MS/MS). The separation was achieved using a 100 mm x 2 mm C8 analytical column combined with an isocratic mobile phase composed of 80:20 acetonitrile: 0.5% formic acid in water. Signal intensity of the propofol-dansyl chloride derivative was increased up to 200-fold as compared to the underivatized propofol in positive electrospray mode. An analytical range of 20-20,000 ng/mL was used in the calibration curve of plasma and blood samples. The novel method met all requirements of specificity, sensitivity, linearity, precision, accuracy and stability. A pharmacokinetic study was performed in rats and the novel analytical method was used as a routine analysis to provide enhanced measurements of plasma and blood concentrations of propofol. Blood and plasma pharmacokinetic results show that a very important fraction of propofol distributes into red blood cells. In conclusion, a rapid and sensitive LC-ESI/MS/MS method using a derivatization agent was developed to enhance signal intensity of propofol. Routine analysis with the novel method provided accurate results and enhanced the detection levels of plasma and blood concentrations of propofol to better characterize the in vivo biodisposition of propofol.

PubMed, Feb 1, 1998

The kinetics of propranolol enantiomers are stereoselective when high doses of the racemic drug a... more The kinetics of propranolol enantiomers are stereoselective when high doses of the racemic drug are given po. To document whether the dose and/or the route of administration determines the stereoselective kinetics of propranolol enantiomers, conscious rabbits received 40, 80, or 120 mg/kg po or 0.5 or 10 mg/kg iv doses of racemic propranolol, and serial blood samples were obtained to assay propranolol enantiomers. At low po and iv doses, the kinetics of the propranolol enantiomers were identical. After the 120 mg/kg po dose, the kinetics of the enantiomers were stereoselective, i.e. the AUC0-->infinity for (S)-(-)-propranolol was greater than the AUC0-->infinity for (R)-(+)-propranolol (p < 0.05). The iv injection of 10 mg/kg generated zero-order kinetics, and (S)-(-)-propranolol was eliminated faster than the antipode. Propranolol enantiomer plasma protein binding was not stereoselective. In vitro, after the incubation of 5.8 or 58 microM (RS)-propranolol with cells of the intestinal mucosa or the liver, (R)-(+)-propranolol was more rapidly metabolized than (S)-(-)-propranolol at both concentrations in the intestine and at the higher concentration in the liver. Incubation of the individual enantiomers (2.9 and 29 microM) showed that in the intestine the intrinsic clearance of (R)-(+)-propranolol was greater than that of (S)-(-)-propranolol but in the liver there was preferential saturation of (S)-(-)-propranolol clearance. In conclusion, at low po or iv doses the kinetics of (RS)-propranolol are not stereoselective because the liver overshadows the effect of the intestine, and at high po doses the kinetics of propranolol enantiomers are stereoselective because of hepatic saturation of (S)-(-)-propranolol clearance.

The Journal of Clinical Pharmacology, Dec 19, 2018

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic rati... more CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, is approved in the United States for adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. Population pharmacokinetics analyses were performed using nonlinear mixed-effect modeling on pooled data from 3 clinical studies,and the impact of CPX-351 exposures on efficacy and safety was assessed. The pharmacokinetics of cytarabine and daunorubicin were described using 2-compartment models with linear elimination. None of the evaluated covariates had a clinically significant impact on plasma exposure to total cytarabine or daunorubicin, while bilirubin and formulation showed statistically significant effects on pharmacokinetic parameters of cytarabine and daunorubicin, respectively. In patients with mild/moderate renal impairment or serum bilirubin ࣘ3 mg/dL, plasma exposures to cytarabine and daunorubicin following CPX-351 were within the variability range for patients with normal kidney function or serum bilirubin levels. Exposure-response analysis demonstrated that better efficacy outcomes were associated with higher CPX-351 exposure quartiles. Early mortality rates in all CPX-351 exposure quartiles were lower vs the 7 + 3 control group, and lower mortality rates were associated with higher exposure quartiles. A trend toward greater frequency of grade 3 treatment-emergent adverse events (but not grade 4/5 events) was observed at higher CPX-351 exposure quartiles. Overall, the population pharmacokinetic analyses indicate no adjustments to the recommended dose and schedule of CPX-351 are warranted for patients with mild/moderate renal impairment or serum bilirubin ࣘ3 mg/dL. Results from the exposure-response analyses suggest the current CPX-351 regimen provides a favorable risk-benefit profile.

Journal of Clinical Pharmacy and Therapeutics, Aug 28, 2013

Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue under evaluation for the tr... more Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue under evaluation for the treatment for pulmonary arterial hypertension (PAH). This study assessed the pharmacokinetics (PK) and safety of treprostinil following oral administration of a single sustained-release 1 mg dose in subjects with hepatic impairment. Four cohorts, including healthy volunteers, and subjects with mild, moderate and severe hepatic impairment were enrolled. Thirty subjects completed the study. Mean treprostinil clearance values (CL/F) decreased with the severity of hepatic impairment. The decrease in CL/F resulted in a marked increase in exposure levels of treprostinil. Relative to healthy subjects, mean area under the curve from time zero to 24 h after dosing interval (AUC0-24) values in subjects with mild, moderate and severe hepatic impairment increased by approximately 2·2-, 4·9- and 7·6-fold, respectively. The most frequent adverse events (AEs) exhibited in this study were similar to those seen with prostacyclin and its analogues and with AEs seen in other clinical studies with oral treprostinil (e.g. headache, diarrhoea and nausea). The overall incidence of all AEs and the specific events of headache and nausea increased with severity of hepatic impairment. Based on these results, dosage adjustments should be performed in subjects with hepatic impairment.

Journal of Pharmacology and Experimental Therapeutics, Jul 1, 2002

Pharmacokinetics of trans-resveratrol in its aglycone (RES AGL) and glucuronide (RES GLU) forms w... more Pharmacokinetics of trans-resveratrol in its aglycone (RES AGL) and glucuronide (RES GLU) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of ␤-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES AGL and RES GLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RE-S AGL and RES GLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RE-S AGL declined with a rapid elimination half-life (T 1/2 , 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES AGL (T 1/2TER , 1.31 h). RES AGL and RES GLU also Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

Clinical Pharmacology & Therapeutics, Feb 1, 2004

International Journal of Clinical Pharmacology and Therapeutics, Apr 1, 2006

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successf... more Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successfully for more than a decade to treat human immunodeficiency virus (HIV) infection. The objective of the current study was to determine the bioequivalence between a generic capsule formulation of efavirenz and the innovator product. A total of 41 healthy subjects (34 males and 8 females) received a single 200 mg oral dose of efavirenz as the generic (Ranbaxy-Efavirenz, Ranbaxy Laboratories Ltd.) and innovator (Sustiva, Bristol-Myers Squibb) capsule formulations under fasting conditions in a randomized, 2-way crossover study. Multiple blood samples were collected over 72 hours and plasma concentrations of efavirenz were assayed using an LC/MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. Plasma concentrations of efavirenz peaked within 2.5 hours and then declined in a multi-exponential manner for both formulations. At 72 hours post dose, all plasma concentrations of efavirenz were above the LOQ of the assay (10 ng/ml). Mean area under the curve from 0 - 72 hours (AUC0-72) and maximum plasma concentrations (Cmax) of efavirenz for the generic capsule formulation were 22,840 ng x h/ml and 1,199 ng/ml, respectively. Ratios and 90% confidence intervals of PK parameters between the two formulations were within 80.0 - 125.0%, suggesting that the two capsule formulations resulted in similar rate and extent of bioavailability under fasting conditions. Adverse events were similar in nature and frequency for the two formulations. Based on the above results, the generic capsule formulation of efavirenz developed by Ranbaxy should be as effective as the innovator product.

International Journal of Clinical Pharmacology and Therapeutics, Jun 1, 2006

Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HI... more Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.

International Journal of Clinical Pharmacology and Therapeutics, May 1, 2006

Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immuno... more Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.

Molecular Genetics and Metabolism, 2020

symptoms are quite burdensome and have a significant impact on the quality of life of MPS I patie... more symptoms are quite burdensome and have a significant impact on the quality of life of MPS I patients. Despite this, many patients fail to receive adequate support services for these aspects of their multisystem condition. The aim of this study was to describe the cognitive, adaptive, behavioral, and fine-motor functioning of MPS I patients diagnosed and treated at the Hospital for Sick Children from 2003 to 2018, based on serial neurocognitive assessments. Of the 15 patients included in this study, 12 had the severe disease phenotype, Hurler syndrome (MPS IH), and 3 had the less severe, attenuated disease form (MPS IA). A large portion of study patients showed notable cognitive impairment (2 SD below average); however, cognitive abilities were relatively stable over time. Patients with MPS IH were at increased risk of adaptive and behavioral skill deficits including irregular socialization patterns and atypical behaviours (e.g. saying/doing nonsensical things, seeming out of touch with reality). Patients with MPS IA presented with less frequent concerns of adaptive and behavioral skill deficits. This study also identified 2 patients (13%) with clinical diagnoses of ASD and 2 (13%) with intellectual disability. Compared to the population prevalence of these psychiatric disorders (ASD: 1/88; intellectual disability: 1/50), this study's rates were considerably higher. Additionally, a high proportion of the MPS IH patients were at risk and/or showed clinically significant adaptive and behavioral skill deficits, both of which are well-documented ASD-like symptoms. These findings are alarming and necessitate further exploration to assess for causation of ASD in MPS I patients to guide improved management strategies, direction for future clinical trials, and ultimately, improved quality of life for patients and their families.