Kyle Matschke

Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Mild to Moderate Hepatic Impairment

Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control subjects were given a single 15‐mg dose of sirolimus by oral solution. Mean whole‐blood sirolimus weight‐normalized oral‐dose clearances (CL/F) were significantly decreased (P = .02) in subjects with mild to moderate hepatic impairment by −31.8% and −36.0%, respectively, compared with controls. There were no significant differences in mean sirolimus Cmax and tmax values among groups. The observed decreases in CL/F may be relevant in renal transplant patients with mild to moderate hepatic impairment, based on the close similarity of sirolimus CL/F in controls and previously studied stable renal transplant patients receiving multiple‐dose administration of sirolimus and cyclosporine. There was considerable overlap in the CL/F values of hepatic‐impaired subjects and controls, suggesting that whole‐blood sirolimus trough concentrations in renal transplant patients exhibiting mild to moderate hepatic impairment be initially monitored to assess the need for dose adjustments.

Evaluation of a Potential Tigecycline‐Warfarin Drug Interaction

Study Objective. To evaluate the potential for a clinically significant drug interaction between tigecycline and warfarin by using pharmacokinetic and anticoagulant assessments.

Relative Bioavailability of Liquid and Tablet Formulations of the Antiparasitic Moxidectin.

The antiparasitic agent moxidectin is under development for the treatment of onchocerciasis. As the first‐in‐human study of moxidectin used a liquid formulation but other trials used tablets, a study was performed to determine the relative bioavailability of the 2 formulations and to gain more information about the pharmacokinetics of moxidectin. Fifty‐eight healthy male participants were randomized to receive open‐label moxidectin (10 mg) as a tablet (n = 29) or liquid (n = 29) formulation. The mean ± SD pharmacokinetic parameters observed following administration of the tablet were peak concentration (Cmax) 67.1 ± 27.4 ng/mL, time to peak concentration (tmax) 3.2 ± 1.4 hours, area under the concentration time curve (AUC) 4403 ± 2360 ng·h/mL, apparent volume of distribution 3635 ± 1720 L, oral clearance 2.83 ± 1.25 L/h, and elimination half‐life 1032 ± 502 hours. The Cmax and AUC observed following administration of the liquid formulation were 28.6% and 28.8% higher, respectively, and tmax 0.9 hours shorter compared with tablets. No serious adverse events (AEs) were observed. The most commonly reported AEs were headache, infection, diarrhea, asthenia, myalgia, and dizziness during the inpatient phase and flu syndrome, headache, and infection during the 6‐month outpatient phase. There was no difference in reporting of these AEs between formulations.

Excretion of Moxidectin into Breast Milk and Pharmacokinetics in Healthy Lactating Women

ABSTRACT Moxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (Cmax), 87 ± 25 ng/ml; time to Cmax (tmax), 4.18 ± 1.59 h; terminal-phase elimination half-life (t1/2), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng·h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/F to the terminal-phase disposition rate constant, λz (Vλz/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CLmilk), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n = 4), oropharyngeal pain (n = 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n = 2).

Absence of an interaction between tigecycline and digoxin in healthy men.

Study Objective. To evaluate a potential interaction between tigecycline and digoxin using pharmacokinetic and pharmacodynamic assessments.

Tigecycline Pharmacokinetics in Subjects With Various Degrees of Renal Function

The pharmacokinetic parameters of tigecycline were assessed in subjects with severe renal impairment (creatinine clearance <30 mL/min, n = 6), subjects receiving hemodialysis (4 received tigecycline before and 4 received tigecycline after hemodialysis), and subjects with age‐adjusted, normal renal function (n = 6) after administration of single 100‐mg doses. Serial serum and urine samples were collected and assayed using validated liquid chromatography with tandem mass spectrometer (LC/MS/MS) methods. Concentration‐time data were then analyzed using noncompartmental pharmacokinetic methods. Tigecycline renal clearance in subjects with normal renal function represented approximately 20% of total systemic clearance. Tigecycline clearance was reduced by approximately 20%, and area under the tigecycline concentration‐time curve increased by approximately 30% in subjects with severe renal impairment. Tigecycline was not efficiently removed by dialysis; thus, it can be administered without regard to timing of hemodialysis. Based on these pharmacokinetic data, tigecycline requires no dosage adjustment in patients with renal impairment.

The effect of a high-fat breakfast on the pharmacokinetics of moxidectin in healthy male subjects: a randomized phase I trial.

The objective of this study was to assess the effect of a high-fat meal on the pharmacokinetics of moxidectin. Healthy male subjects were randomized to receive single oral 8 mg doses of moxidectin after an overnight fast or high-fat breakfast. In fasted subjects (N = 27), mean [SD] parameters were Cmax: 58.9 [12.5] ng/mL; tmax: 3.7 [1.5] h; area under concentration-time curve (AUC): 3,387 [1,328] ng/h/mL; Vλz/F: 2,829 [1,267] L; CL/F: 2.76 [1.28] L/h; and t½: 784 [347] h. Compared with fasted subjects, fed subjects (N = 27) exhibited a 34% increase in Cmax, delay in tmax to 5.3 [2.1] h, 44% increase in AUC, 40% decrease in Vλz/F, and a 35% decrease in CL/F. There was no significant change in t½. The changes are consistent with an increase in moxidectin bioavailability following administration with food. There were no clinically relevant changes in vital signs, laboratory tests, or electrocardiograms.

Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Severe Hepatic Impairment

Nine subjects with severe hepatic impairment (Child‐Pugh grade C) and 9 healthy matched control subjects were given a single 15‐mg dose of sirolimus by oral solution. Increases (P ≥ .002) in mean whole‐blood sirolimus t1/2 (168%), AUC0‐∞ (210%), and MRToral (261%), together with a decrease (P = .001) in CL/F (−67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child‐Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter‐study comparison. Overall, mean t1/2, weight‐normalized AUC, and MRToral increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO‐02 is an abuse‐deterrent formulation consisting of capsules filled with pellets of extended‐release oxycodone surrounding sequestered naltrexone. This randomized, double‐blind, placebo‐/active‐controlled, 4‐way crossover study examined the abuse potential of crushed ALO‐02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4‐way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO‐02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate‐release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax) and effect occurring over 2 hours postdose (AUE0–2 h). Crushed ALO‐02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax, 60.5 vs 92.8; AUE0–2 h, 105.4 vs 160.0, respectively) and High (Emax, 25.2 vs 86.9; AUE0–2 h, 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO‐02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO‐02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

A Phase 1, Randomized, Placebo‐ and Active‐Controlled Crossover Study to Determine the Effect of Single‐Dose Ertugliflozin on QTc Interval in Healthy Volunteers

Ertugliflozin, a selective sodium‐glucose cotransporter‐2 inhibitor, is being developed for the treatment of type 2 diabetes mellitus. This randomized, 6‐sequence, 3‐period crossover study assessed the effect of ertugliflozin (100 mg; supratherapeutic dose) vs placebo and moxifloxacin (400 mg; positive control) on the QT interval corrected for heart rate (QTc) in 42 male or female healthy subjects. Triplicate electrocardiograms were performed predose and serially over 48 hours postdose in each treatment period. The maximum observed least‐squares mean (90% CI) difference in QTc using the Fridericia correction (QTcF) between ertugliflozin and placebo was 2.99 (1.68, 4.30) milliseconds, 24 hours postdose, below the 5‐millisecond threshold of potential clinical concern. The upper limits of the 2‐sided 90% CI were less than 10 milliseconds at all postdose time points. The lower 90% CIs for the least‐squares mean QTcF difference between moxifloxacin and placebo were greater than 5 milliseconds at the preselected time points of 2, 3, and 4 hours postdose, establishing study sensitivity. The majority of adverse events were mild in severity. In healthy volunteers, at a supratherapeutic dose of 100 mg, ertugliflozin was not associated with QTc interval prolongation.