Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics.

Pexidartinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase enzymes, with ZAAD-1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib.

A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment.

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P-gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (C ), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2-fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed.

Pharmacokinetics and Safety of the Novel Selective Progesterone Receptor Modulator Vilaprisan in Participants With Renal Impairment.

This open label, parallel-group study investigated the pharmacokinetics and safety of a single oral 2-mg dose of the novel selective progesterone receptor modulator vilaprisan in participants with impaired renal function compared with age, weight, sex, and race matched controls with normal renal function. Systemic exposure (area under the plasma concentration-time curve [AUC]) and maximum observed concentrations (C ) were compared among 9 participants with moderate renal impairment and matched controls by ANOVA. An additional 4 participants, each with severe renal impairment or normal renal function, contributed to a linear regression analysis exploring any monotone relationship between individual variables and the estimated glomerular filtration rate.

Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment.

Background: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection.

Objective: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment.

Methods: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study.

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

Introduction: Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.

Methods: These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.

Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics.

Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects.

Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects.

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0.5 mg; P-gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.

Influence of renal and hepatic impairment on the pharmacokinetics of anacetrapib.

Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl <30 mL/min/1.73 m(2)).

The effect of rifampin on the pharmacokinetics of sirolimus in healthy volunteers.

Sirolimus, metabolized primarily by intestinal and hepatic CYP3A4, is a substrate for P-glycoprotein. CYP3A4 inducers would be expected to decrease sirolimus exposure. This open-label, nonrandomized study investigated effects of CYP3A4 induction, by rifampin, on sirolimus pharmacokinetics.

Evaluation of the single-dose pharmacokinetics of bilastine in subjects with various degrees of renal insufficiency.

Background: Bilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries.

Objective: This study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects.

The effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin, a novel sodium glucose co-transporter 2 (SGLT2) inhibitor.

Background: Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.

The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study.

Objectives: The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and prasugrel therapy.

Background: Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e.

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.

Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.

Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women).

Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis.

Nebivolol withdrawal results in blood pressure returning toward pretreatment levels, but without rebound symptoms: phase IV randomized trial.

Rapid withdrawal of antihypertensive drugs may lead to blood pressure (BP) increase above pretreatment values or symptoms such as palpitations, chest pain, and tremor. This phase IV trial assessed the consequences of abrupt and stepwise withdrawal of nebivolol, a β(1)-selective blocker, in individuals with stage I-II hypertension. After a 4- to 5-week placebo washout phase and 12-week single-blind nebivolol treatment (10-40 mg/day, titrated based on BP response), participants achieving BP control (systolic BP [SBP]/diastolic BP [DBP] <140/90 mm Hg) or response (SBP decrease ≥10 mm Hg or DBP decrease ≥5 mm Hg) entered a 4-week, randomized, double-blind phase of continued nebivolol treatment (n = 102) or withdrawal to placebo (n = 105).

Segmental bioimpedance for measuring amlodipine-induced pedal edema: a placebo-controlled study.

Background: The development of antihypertensives requires efficient and accurate tools for identifying pedal edema. Methodologies used to gauge the potential of an agent to induce pedal edema in short-term (<4-week) clinical trials have not been reported in the literature.

Objective: The purpose of this study was to identify a robust and practical method for measuring drug-induced pedal edema for use in the clinical development of antihypertensives.

Pharmacokinetics of oral tonapofylline and its acyl-glucuronide metabolite in patients with mild and moderate hepatic impairment.

The objective of the study was to evaluate the effect of hepatic impairment on the pharmacokinetics of tonapofylline. Patients with mild or moderate hepatic impairment were enrolled in parallel with demographically matched healthy subjects. All study participants received a single 75-mg oral tonapofylline capsule.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not affect the pharmacokinetics of ethinyl estradiol or norethindrone in healthy female subjects.

Sitagliptin is a dipeptidyl peptidase-IV (DPP-4) inhibitor used for the treatment of patients with type 2 diabetes mellitus. This randomized, placebo-controlled, 2-period, crossover study evaluated the effect of sitagliptin on the pharmacokinetics of 17 α-ethinyl estradiol (EE(2)) and norethindrone (NET) in healthy female subjects who were receiving oral contraceptives for >3 months prior to enrollment. A total of 18 subjects with normal menstrual cycles received the oral contraceptive pill ORTHO-NOVUM(®) 7/7/7 on days 1 to 28 for 2 successive cycles, and on days 1 to 21 were randomly assigned to receive sitagliptin 200 mg/day (2 × 100 mg tablets) or placebo using a computer-generated allocation schedule.

Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects.

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 µg, aclidinium 800 µg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI).

Pharmacokinetics of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, in patients with moderate hepatic impairment.

This open-label study evaluated the influence of hepatic insufficiency on the pharmacokinetics of laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist, to guide clinicians in the event of inadvertent dosing in patients with hepatic insufficiency. A single oral 40-mg dose of LRPT was administered to 8 patients with moderate hepatic insufficiency and 8 healthy control participants matched for important baseline characteristics. Blood samples were collected predose and up to 96 hours postdose to assess LRPT pharmacokinetics.

Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Aims: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib.

Methods: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated.

Effects of omeprazole on the pharmacokinetic profiles of lisdexamfetamine dimesylate and extended-release mixed amphetamine salts in adults.

Objective: To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant, and mixed amphetamine salts extended-release (MAS XR), alone or with omeprazole, a proton pump inhibitor (PPI).

Methods: This open-label, randomized, 4-period crossover study enrolled healthy adults (18-45 years). Subjects alternately received single doses of LDX 50 mg and MAS XR 20 mg at 4-day intervals.

Influence of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the pharmacokinetics and pharmacodynamics of warfarin.

Laropiprant (LRPT), a prostaglandin D2 receptor 1 antagonist shown to reduce niacin-induced flushing symptoms, is being developed in combination with niacin for the treatment of dyslipidemia. This study assessed the pharmacokinetics/pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose LRPT. Thirteen subjects received 2 treatments in random order separated by > or =10-day washout: (1) multiple-dose LRPT 40 mg/d for 12 days (days -5 to 7) with coadministered single-dose warfarin 30 mg (day 6) and (2) single-dose warfarin 30 mg (day 1).

Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics.

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.

Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.

Background: Sitagliptin is a highly selective dipeptidyl peptidase-4 inhibitor for the treatment of patients with type 2 diabetes. Sitagliptin is primarily excreted by renal elimination as unchanged drug, with only a small percentage (approximately 16%) undergoing hepatic metabolism.

Objectives: The primary purpose of this study was to evaluate the influence of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.