Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants.

Co-administration of clesacostat (acetyl-CoA carboxylase inhibitor, PF-05221304) and ervogastat (diacylglycerol O-acyltransferase inhibitor, PF-06865571) in laboratory models improved non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) end points and mitigated clesacostat-induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time-dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer-term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non-randomized, open-label, fixed-sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1-7) and co-administered with ervogastat 300 mg b.i.d. (Days 8-14). Mean systemic clesacostat exposures, when co-administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration-time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1-7) and co-administered with clesacostat 15 mg b.i.d. (Days 8-14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.

Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough QT Study.

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2-sided 90% confidence intervals (CIs) for all time-matched least-squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure-response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model-derived baseline and placebo-adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5-8.2 milliseconds) and 13.7 milliseconds (12.0-15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20-millisecond threshold of clinical concern in oncology.

Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-ß Peptides in Randomized Phase I Studies.

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-ß (Aß) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aß species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Aß42 and Aß40 concentrations in CSF, with greater effects on Aß42, and increased Aß37 and Aß38 levels, particularly Aß37. No significant change in total Aß was observed. The PK/PD model well described the tendency of observed CSF Aß data and the steady-state effects of PF-06648671, supporting its use for predicting central Aß effects and optimal dose selection for GSMs in future trials.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

BACKGROUND: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. OBJECTIVES: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). METHODS: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. RESULTS: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 µg (range, 270-1720 µg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. CONCLUSION: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. DECLARATION OF CONFLICTING INTERESTS: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. FUNDING: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

Pharmacokinetic interaction between maraviroc and fosamprenavir-ritonavir: an open-label, fixed-sequence study in healthy subjects.

This open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ, Cmax, and Cτ were increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ, Cmax, and Cτ decreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.