Effect of Hepatic Impairment on the Pharmacokinetics of Nirmatrelvir/Ritonavir, the First Oral Protease Inhibitor for the Treatment of COVID-19.

Nirmatrelvir, a novel, potent, orally bioavailable severe acute respiratory syndrome coronavirus 2 main protease inhibitor, coadministered with ritonavir for pharmacokinetic (PK) enhancement is licensed for the treatment of mild to moderate COVID-19 in individuals at increased risk of progression to severe disease. Cytochrome P450 3A4 is the primary metabolic enzyme responsible for nirmatrelvir metabolism; however, when cytochrome P450 3A4 is inhibited by ritonavir, nirmatrelvir is primarily excreted, unchanged, in urine. Because of intended use of nirmatrelvir among individuals with hepatic impairment, this Phase 1 study (NCT05005312) evaluated the effects of hepatic impairment on nirmatrelvir PK parameters to assess the potential need for any dose adjustments in this population. Participants with normal hepatic function or moderate hepatic impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose, with 100 mg of ritonavir administered 12 hours before, together with, and 12 and 24 hours after nirmatrelvir. Nirmatrelvir median plasma concentrations and systemic exposure measured by area under the plasma concentration-time curve from time zero extrapolated to infinite time and maximum observed plasma concentration values were comparable in both groups. Nirmatrelvir/ritonavir had an acceptable safety profile in both groups, and no clinically significant changes in laboratory measurements, vital signs, or electrocardiogram assessments were observed. Based on these results, no dose adjustment is deemed necessary in patients with moderate hepatic impairment and, by extension, in patients with mild hepatic impairment.

Pharmacokinetics of Lapatinib, a Nonrenally Cleared Drug, in Patients With End-Stage Renal Disease on Maintenance Hemodialysis.

Lapatinib, a tyrosine kinase inhibitor, is approved for the treatment of breast cancer. The literature shows that it is metabolized by CYP3A4 and eliminated predominantly (>90%) by the fecal route, with minimal (<2%) renal elimination in healthy subjects (dose of 250 mg); in cancer patients, renal elimination is minimal at therapeutic doses. For nonrenally cleared drugs, while there is ample evidence of pharmacokinetic alterations secondary to renal impairment-induced effects on drug metabolizing enzymes and/or transporters, the effect of end-stage renal disease (ESRD) on lapatinib pharmacokinetics has not been determined. Rather, as stated in the drug's label, the expectation is lack of effect of renal impairment on lapatinib pharmacokinetics based on its minimal renal elimination. The current report addresses this gap with pharmacokinetic data (obtained in a 1-way drug interaction study) in ESRD patients (n = 11) on maintenance hemodialysis and compared with published data in 37 healthy subjects in 3 separate studies. Following a 250-mg oral dose in ESRD patients, the median tmax was 3.0 hours, and geometric mean (95%CI) values for Cmax , AUCinf , and t1/2 were 349 ng/mL (245-499 ng/mL), 4410 ng·h/mL (2960-6580 ng·h/mL), and 14.8 hours (9.7-22.5 hours), respectively. These parameters approximated published values in healthy subjects and demonstrated that renal impairment and hemodialysis did not affect lapatinib pharmacokinetics. The results of the present study in this renally impaired population, the only such information available to date, support the drug's label and are valuable in view of the recognized difficulties in enrolling organ-impaired patients in oncology trials.

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function.

PURPOSE: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. METHODS: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y12 reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. RESULTS: Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (Cmax) and area under the plasma concentration curve from time zero to infinity (AUC0-∞) of ticagrelor were 598.4 ng/mL and 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. Cmax and AUC0-∞ of AR-C124910XX, the active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. CONCLUSION: Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA.

Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment.

Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram-negative bacteria including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000-mg intravenous 1-hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half-life (t1/2 ) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration-time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8-1.3), 1.5 (1.2-1.9), 2.5 (2.0-3.3), and 4.1 (3.3-5.2), respectively. Maximum plasma concentration (Cmax ) was similar between renal-impairment groups and the normal-renal-function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma-protein-unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000-mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax . Cefiderocol was significantly removed by intermittent hemodialysis.

A randomized, double-blind, placebo-controlled, multiple-dose, parallel-group clinical trial to assess the effects of teduglutide on gastric emptying of liquids in healthy subjects.

BACKGROUND: Teduglutide, a recombinant analog of human glucagon-like peptide (GLP)-2, is a novel therapy recently approved for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. Previous studies assessing the effect of GLP-2 on gastric emptying in humans have yielded inconsistent results, with some studies showing no effect and others documenting a GLP-2-dependent delay in gastric emptying. The primary objective of this study was to assess the effect of teduglutide on gastric emptying of liquids in healthy subjects, as measured by the pharmacokinetics of acetaminophen. METHODS: This double-blind, parallel-group, single-center study enrolled and randomized 36 healthy subjects (22 men, 14 women) to receive subcutaneous doses of teduglutide 4 mg or placebo (2:1 ratio; 23:13) once daily on Days 1 through 10 in the morning. Gastric emptying of a mixed nutrient liquid meal was assessed by measuring acetaminophen levels predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, and 14 hours after administration of 1000 mg acetaminophen on Days 0 and 10. The primary study endpoint was a pharmacokinetic analysis of acetaminophen absorption in subjects receiving teduglutide or placebo. RESULTS: No significant differences in gastric emptying of liquids (acetaminophen area under the concentration [AUC] vs time curve from time 0 to the last measurable concentration, AUC extrapolated to infinity, maximum concentration [Cmax], and time to Cmax) were observed on Day 10 in subjects receiving teduglutide 4 mg versus subjects receiving placebo. There were no serious adverse events (AEs), deaths, or discontinuations due to an AE reported during the study. CONCLUSIONS: Teduglutide 4 mg/day for 10 days does not affect gastric emptying of liquids in healthy subjects as measured by acetaminophen pharmacokinetics. No unexpected safety signals were observed. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT01209351.