Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin.

AIMS: Two phase 1, open-label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI). METHODS: Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults. RESULTS: Geometric mean ratios (RI/healthy matched controls) of area under the concentration-time curve from time 0 to infinity (AUC0-∞ ; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half-life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events. CONCLUSION: RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed-ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem.

Assessment of the Effect of Pyrimethamine, a Potent Inhibitor of Multidrug and Toxin Extrusion Protein 1/2K, on the Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist.

Gefapixant (MK-7264, AF-219) is a first-in-class P2X3 antagonist in development for refractory or unexplained chronic cough. Gefapixant is primarily cleared by renal excretion. To assess the importance of the multidrug and toxin extrusion protein 1 (MATE1) and MATE2K transporters in the elimination of gefapixant, a drug-drug interaction study was conducted evaluating the effect of coadministration of a single dose of pyrimethamine, a competitive inhibitor of MATE1 and MATE2K, on the single-dose pharmacokinetics of gefapixant in healthy participants. Safety and tolerability were also assessed. In this open-label, 2-period, fixed-sequence study, a 45-mg dose of gefapixant was administered to 12 participants in period 1. After a 7-day washout, a 50-mg dose of pyrimethamine was administered 3 hours before a 45-mg dose of gefapixant in period 2. Compared with the administration of gefapixant alone, concomitant dosing of gefapixant with pyrimethamine increased the total gefapixant plasma exposure (area under the plasma concentration-time curve from time 0 to infinity) by 24%, reduced gefapixant renal clearance by 30%, and increased gefapixant mean terminal half-life from 7.7 to 10.3 hours. The most frequently reported adverse events were dysgeusia, hypogeusia, and dry mouth; all adverse events were considered of mild intensity and resolved by the end of the study. These results support that MATE1 and/or MATE2K contribute to the renal clearance of gefapixant, but the effect of inhibition of these transporters on gefapixant pharmacokinetics is not considered clinically meaningful.

Assessment of Pharmacokinetic Interaction Between Gefapixant (MK-7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin.

Gefapixant (MK-7264, AF-219), a first-in-class P2X3 antagonist, is being developed as oral treatment for refractory or unexplained chronic cough. Based on in vitro data, gefapixant exerts inhibitory activity on the organic anion transporter (OAT) P1B1 transporter. Therefore, a drug-drug interaction study evaluating the potential effects of gefapixant on the OATP1B1 drug transporter, using pitavastatin as a sensitive probe substrate, was conducted. An open-label, 2-period, fixed-sequence study in 20 healthy adults 18 to 55 years old was conducted. In period 1, a 1-mg oral dose of pitavastatin was administered to each participant. After a ≥4-day washout, in period 2 participants received a 45-mg oral dose of gefapixant twice daily on days 1 through 4. On day 2 of period 2, pitavastatin was coadministered with the morning dose of gefapixant. Pitavastatin exposures following single-dose administration with and without multiple doses of gefapixant were similar: geometric mean ratio (90% confidence interval) of pitavastatin area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) (pitavastatin + gefapixant/pitavastatin alone) was 0.97 (0.93-1.02). The ratio of pitavastatin lactone AUC0-∞ to pitavastatin AUC0-∞ was also comparable between treatments. Administration of gefapixant and pitavastatin was generally well tolerated, with no safety findings of concern. These results support that gefapixant has a low potential to inhibit the OATP1B1 transporter.

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. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration-time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (C max), respectively. The observed median time to C max was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. CONCLUSIONS: The pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non-HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

Absorption, metabolism, and excretion of [(14)C]MK-0524, a prostaglandin D(2) receptor antagonist, in humans.

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [(14)C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 microCi). [(14)C]MK-0524 was absorbed rapidly, with plasma C(max) achieved 1 to 1.5 h postdose. The major route of excretion of radioactivity was via the feces, with 68% of the administered dose recovered in feces. Urinary excretion averaged 22% of the administered dose, for a total excretion recovery of approximately 90%. The majority of the dose was excreted within 96 h following dosing. Parent compound was the primary radioactive component circulating in plasma, comprising 42 to 72% of the total radioactivity in plasma for up to 12 h. The only other radioactive component detected in plasma was M2, the acyl glucuronic acid conjugate of the parent compound. The major radioactive component in urine was M2, representing 64% of the total radioactivity. Minor metabolites included hydroxylated epimers (M1/M4) and their glucuronic acid conjugates, which occurred in the urine as urea adducts, formed presumably during storage of samples. Fecal radioactivity profiles mainly comprised the parent compound, originating from unabsorbed parent and/or hydrolyzed glucuronic acid conjugate of the parent compound. Therefore, in humans, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE: To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS: Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS: Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION: Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.