Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis.

BACKGROUND: H4 receptor antagonists are potential novel treatments for inflammatory skin diseases, including atopic dermatitis (AD). OBJECTIVE: We sought to study the efficacy and safety of ZPL-3893787 (a selective H4 receptor antagonist) in patients with moderate-to-severe AD. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate ZPL-3893787 (30 mg) once-daily oral therapy in adults with moderate-to-severe AD. Patients were randomized (2:1) to ZPL-3893787 (n = 65) or placebo (n = 33) for 8 weeks. Patients had a history of AD for more than 12 months, Eczema Area and Severity Index (EASI) scores of 12 or greater and 48 or less, Investigator's Global Assessment (IGA) scores of 3 or greater, pruritus scores of 5 or greater (0- to 10-point scale), and AD on 10% or greater of body surface area. Efficacy parameters included EASI, IGA, SCORAD, and pruritus assessment. RESULTS: Treatment with oral ZPL-3893787 showed a 50% reduction in EASI score compared with 27% for placebo. The placebo-adjusted reduction in EASI score at week 8 was 5.1 (1-sided P = .01). Clear or almost-clear IGA scores were 18.5% with ZPL-3893787 versus 9.1% with placebo. SCORAD scores exhibited 41% reduction with ZPL-3893787 versus 26% with placebo (placebo-adjusted reduction of 10.0, P = .004). There was a 3-point reduction (scale, 1-10) in pruritus with ZPL-3893787, but there was a similar reduction with placebo, resulting in a nonsignificant difference (P = .249). Patient-reported pruritus subscores obtained from SCORAD were reduced with ZPL-3893787 compared with placebo at week 8 (nonsignificant). ZPL-3893787 was well tolerated. CONCLUSION: For the first time, these results showed that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H4 receptor antagonism as a novel therapeutic option.

Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers.

AIMS: To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive. METHODS: Three randomized, double-blind, placebo-controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two-period crossover studies were conducted to assess (i) the effect of steady-state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady-state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two-way crossover study was conducted to evaluate the effect of steady-state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 microg ethinyloestradiol/150 microg levonorgestrel (Microgynon). RESULTS: The geometric mean ratios for C(max) and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in T(max), t(1/2) or CL(R) (where measured) for any of the compounds. CONCLUSIONS: Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.

Effects of CYP3A4 inducers with and without CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers.

AIMS: To assess the potential of known CYP3A4 inducers, with and without CYP3A4 inhibitors, to alter the pharmacokinetic profile of maraviroc. METHODS: Two separate, open, randomized, placebo-controlled studies were conducted in healthy subjects. Study 1 was a 28-day parallel-group study with three treatment groups of 12 subjects each. On days 1-7, all subjects received maraviroc 100 mg b.i.d.; on days 8-21, subjects received maraviroc 100 mg b.i.d. plus either rifampicin 600 mg q.d., efavirenz (EFV) 600 mg q.d., or placebo q.d. as assigned; on days 22-28, the maraviroc dose was increased to 200 mg b.i.d. for patients receiving either rifampicin or EFV. Study 2 was a 21-day, two-way crossover study with three cohorts (12 subjects per cohort). On days 1-21, subjects received maraviroc 300 mg b.i.d. and boosted lopinavir (LPV/r, lopinavir 400 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 1, maraviroc 100 mg b.i.d. and boosted saquinavir (SQV/r, saquinavir 1000 mg + ritonavir 100 mg) or placebo b.i.d. in cohort 2, and maraviroc 100 mg b.i.d. and 1000 mg saquinavir + LPV/r (400 mg/100 mg) or placebo b.i.d. in cohort 3. On days 8-21, subjects in all three cohorts also received EFV 600 mg or placebo q.d. RESULTS: Maraviroc (100 mg b.i.d.) exposure (AUC(12) and C(max)) was reduced in the presence of rifampicin and EFV by approximately 70% and 50%, respectively. Maraviroc AUC(12) and C(max) approached preinduction values when the maraviroc dose was increased to 200 mg b.i.d. for both the rifampicin-treated and EFV-treated groups. Co-administration of LPV/r with maraviroc (300 mg b.i.d.) resulted in geometric mean ratios (GMRs) of 395% and 197% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 253% and 125% for AUC(12) and C(max), respectively. Co-administration of SQV/r with maraviroc (100 mg b.i.d.) resulted in GMRs of 977% and 478% for maraviroc AUC(12) and C(max), respectively, compared with placebo; addition of EFV resulted in GMRs of 500% and 226% for AUC(12) and C(max), respectively. No pharmacokinetic data are reported for cohort 3 because all subjects were discontinued during period 1 due to poor toleration of the drug regimen. There were no serious adverse events reported in either study, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSION: As expected with a CYP3A4 substrate, maraviroc exposure (C(max) and AUC(12)) was significantly reduced by the known CYP3A4 inducers, rifampicin and EFV, by approximately 70% and 50%, respectively. Upward adjustment of the maraviroc dose during co-administration with rifampicin or EFV appears to compensate for this reduction. Protease inhibitors (PIs) significantly increased maraviroc exposure; however, the addition of EFV to the maraviroc + PI regimens reduced the magnitude of PI-mediated increase in maraviroc exposure (by approximately 50%), but the net effect was still CYP3A4 inhibition.

The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers.

AIMS: To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of maraviroc. METHODS: Two randomized, placebo-controlled, two-way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18-45 years, received maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21-45 years, received maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1-7. In study 2, blood was collected predose, on day 1 and days 3-7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0-12 h post morning dose. Blood and urine were analysed for maraviroc using liquid chromatography/tandem mass spectrometry. RESULTS: The geometric mean ratios for C(max) and AUC(12) were 119% and 111%, respectively, for maraviroc plus cotrimoxazole and 104% and 103%, respectively, for maraviroc plus tenofovir, compared with maraviroc plus placebo. Renal clearance of maraviroc plus placebo was 8.3 l h(-1) and 8.5 l h(-1) and was 7.8 l h(-1) for maraviroc plus cotrimoxazole and maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms. CONCLUSIONS: Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co-administered with either cotrimoxazole or tenofovir.

Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.

AIMS: Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc. METHODS: Study 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of (14)C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only. RESULTS: After oral administration in study 1, maraviroc was rapidly absorbed with a plasma T(max) reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio approximately 0.6 for AUC(t) and C(max)). Unchanged maraviroc was the major circulating component in plasma, accounting for approximately 42% of the circulating radioactivity. Following a 300-mg (14)C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h(-1)) was accounted for by renal clearance (10.2 l h(-1)). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%. CONCLUSIONS: Maraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.