Population pharmacokinetic characteristics of cemiplimab in patients with advanced malignancies.

Cemiplimab, a human monoclonal antibody targeting programmed cell death-1 (PD-1) receptor, demonstrated antitumor activity in patients with advanced malignancies and a safety profile comparable to other anti-PD-1 therapies. This population pharmacokinetics (PopPK) analysis of cemiplimab included 11,178 pharmacokinetics (PK) observations from 548 patients pooled from a first-in-human study (Study 1423; NCT02383212) in advanced malignancies and a Phase 2 study (Study 1540; NCT02760498) in advanced cutaneous squamous cell carcinoma (CSCC). Most patients (80.3%) received cemiplimab 3 mg/kg every 2 weeks (Q2W) intravenously (IV). A PopPK model was developed by evaluating two-compartment linear models with an empirical non-linear function describing time-varying change in cemiplimab clearance and covariates that improved goodness-of-fit. PopPK simulations were used to describe cemiplimab exposure generated by a fixed 350 mg every 3 weeks (Q3W) IV dose regimen. PopPK modeling showed that a two-compartment model with zero-order IV infusion rate and first-order elimination rate well described individual concentrations of cemiplimab. Although several covariates, including baseline body weight and albumin concentrations, had a modest impact on cemiplimab exposure, the magnitude of influence was within the typical observed PK variability of approximately 30%. Based on PopPK simulation results, the 350 mg Q3W dose regimen was selected for further studies in advanced malignancies, including advanced CSCC. Similarity in observed cemiplimab exposure at the fixed 350 mg Q3W and the weight-based 3 mg/kg Q2W dose regimens confirmed this fixed dose selection. A robust PopPK model was developed to describe cemiplimab concentrations and supported use of the fixed 350 mg Q3W IV dose regimen.

Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis.

INTRODUCTION: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498). METHODS: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values. RESULTS: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations. CONCLUSIONS: Cemiplimab 350 mg Q3W is being further investigated in multiple indications.

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects.

INTRODUCTION: Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. METHODS: Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. RESULTS: Telcagepant was rapidly absorbed with a T(max) of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. CONCLUSIONS: Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics.

Metabolism and renal elimination of gaboxadol in humans: role of UDP-glucuronosyltransferases and transporters.

PURPOSE: Gaboxadol, a selective extrasynaptic agonist of the delta-containing gamma-aminobutyric acid type A (GABAA) receptor, is excreted in humans into the urine as parent drug and glucuronide conjugate. The goal of this study was to identify the UDP-Glucuronosyltransferase (UGT) enzymes and the transporters involved in the metabolism and active renal secretion of gaboxadol and its metabolite in humans.Methods. The structure of the glucuronide conjugate of gaboxadol in human urine was identified by LC/MS/MS. Human recombinant UGT isoforms were used to identify the enzymes responsible for the glucuronidation of gaboxadol. Transport of gaboxadol and its glucuronide was evaluated using cell lines and membrane vesicles expressing human organic anion transporters hOAT1 and hOAT3, organic cation transporter hOCT2, and the multidrug resistance proteins MRP2 and MRP4.Results. Our study indicated that the gaboxadol-O-glucuronide was the major metabolite excreted in human urine. UGT1A9, and to a lesser extent UGT1A6, UGT1A7 and UGT1A8, catalyzed the O-glucuronidation of gaboxadol in vitro. Gaboxadol was transported by hOAT1, but not by hOCT2, hOAT3, MRP2, and MRP4. Gaboxadol-O-glucuronide was transported by MRP4, but not MRP2.Conlusion. Gaboxadol could be taken up into the kidney by hOAT1 followed by glucuronidation and efflux of the conjugate into urine via MRP4.

Human pharmacokinetics and interconversion of enantiomers of MK-0767, a dual PPARalpha/gamma agonist.

MK-0767, a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, has been studied as a potential treatment of type 2 diabetes and dyslipidemia. The pharmacokinetics and interconversion of (+)-(R)-MK-0767 and (-)-(S)-MK-0767 were evaluated following oral administration of each single enantiomer and the racemate to healthy subjects. The results demonstrate that, consistent with in vitro experiments, chiral inversion occurs rapidly in vivo, and interconversion equilibrium favors (+)-(R). After all treatments, a stable ratio (R/S) of 2 to 2.5 was achieved within 8 hours in most individuals, congruent with model-based estimates of interconversion half-life. In addition, the pharmacokinetics of each enantiomer were generally similar regardless of treatment. Modeling and simulation of enantiomer disposition suggest that the observed predominance of (+)-(R)-MK-0767 in plasma may result from differential volumes of distribution between (-)-(S) and (+)-(R), preferential conversion from (-)-(S) to (+)-(R), or a combination of these, but not faster clearance of (-)-(S) compared to (+)-(R).

Absorption, metabolism, and excretion of [14C]MK-0767 (2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in humans.

MK-0767 (KRP-297; 2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) is a thiazolidinedione (TZD)-containing dual agonist of the peroxisome proliferator-activated receptors alpha and gamma that has been studied as a potential treatment for patients with type 2 diabetes. The metabolism and excretion of [14C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 microCi) oral dose. Excretion of 14C radioactivity was found to be nearly equal into the urine (approximately 50%) and feces (approximately 40%). Elimination of [14C]MK-0767 was primarily by metabolism, with minimal excretion of parent compound into the urine (<0.5% of dose) and feces (approximately 14% of the dose). [14C]MK-0767 was the major circulating compound-related entity (>96% of radioactivity) through 48 h postdose. It was also found that approximately 91% of the total radioactivity area under the curve was due to intact MK-0767. Several minor metabolites were detected in plasma (<1% of radioactivity, each), formed by cleavage of the TZD ring and subsequent S-methylation and oxidation. All the metabolites excreted into urine were formed by TZD cleavage, whereas the major metabolite in feces was the O-demethylated derivative of MK-0767.

A dual PPAR alpha/gamma agonist increases adiponectin and improves plasma lipid profiles in healthy subjects.

BACKGROUND: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, following administration of single and multiple oral doses in healthy male subjects. METHODS: The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of 1-80 mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3-25 mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. RESULTS: Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged approximately 36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following approximately 8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (-26 +/- 8% [p = 0.002] and -33 +/- 13% [p = 0.008]) and free fatty acids (-50 +/- 11% [p < 0.001] and -67 +/- 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p < or = 0.050) dose-dependent alterations in adiponectin (332 +/- 36%), low-density lipoprotein cholesterol (-29 +/- 5%), total cholesterol (-19 +/- 3%), non-high-density lipoprotein cholesterol (-28 +/- 4%), and fasting plasma glucose (-6 +/- 2%; only in the 25 mg group) were observed after multiple doses. CONCLUSIONS: The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR alpha/gamma agonist has clinically meaningful activity in vivo.

Quantitative determination of a novel insulin sensitizer and its para-hydroxylated metabolite in human plasma by LC-MS/MS.

I, 5-[3-[3-(4-phenoxy-2-propylphenoxy)-propoxy]-phenyl]-2,4-thiazolidinedione sodium salt, is a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist for potential use in diabetic patients. The compound has a para-hydroxylated metabolite, II, which has also been shown to exhibit PPAR activity. An LC-MS/MS method for the simultaneous determination of I and its active metabolite (II) in human plasma has been successfully developed. The method consists of treating 0.5 ml plasma with ammonium acetate (pH 9.6; 50mM) and extracting I, II and internal standard (III, Fig. 2) with 5 ml ethyl acetate. The ethyl acetate is evaporated and the samples are reconstituted in 0.1 ml acetonitrile:0.1% formic acid (65:35, v/v). The entire extraction procedure, as well as sample collection, was performed in glass tubes and vials to overcome the analytes adherence to polypropylene. A linear HPLC gradient was used to separate the analyte, metabolite, internal standard, and other interfering, non-quantitated metabolites. Detection was by negative ionization MS/MS on a turbo ionspray probe. Precursor-->product ion combinations were monitored in multiple reaction monitoring (MRM) mode. The linear range is 0.05-20 ng/ml for I and 0.1-20 ng/ml for II. Recoveries were 59.4, 90.1 and 56.8% for I, II and III, respectively. Intraday variation using this method was <==7.0% for I and <==9.2% for II. The method exhibits good linearity and reproducibility for each analyte and good sensitivity, selectivity and robustness when used for the analysis of clinical samples.