Bhavna Kantesaria

Hypothalamic-Pituitary-Adrenal Axis Effects of Mometasone Furoate/Formoterol Fumarate vs Fluticasone Propionate/Salmeterol Administered Through Metered-Dose Inhaler

BACKGROUND The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products. METHODS In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 μg/10 μg, MF/F 400 μg/10 μg, fluticasone propionate/salmeterol (FP/S) 460 μg/42 μg, or placebo. Plasma cortisol concentrations were measured over 24 h on days -1 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable. RESULTS Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 μg/10 μg and FP/S 460 μg/42 μg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 μg/10 μg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 μg/10 μg and FP/S 460 μg/42 μg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated. CONCLUSIONS MF/F 400 μg/10 μg or FP/S 460 μg/42 μg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 μg/10 μg was similar to placebo.

Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P‐glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single‐dose POS 300 mg was administered alone, followed by a 7‐day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19‐mediated drug‐drug interactions.

An evaluation of the systemic bioavailability of mometasone furoate (MF) after oral inhalation from a MF/formoterol fumarate metered‐dose inhaler versus an MF dry‐powder inhaler in healthy subjects

This randomized, open‐label, multiple‐dose, two‐period, crossover study compared the systemic bioavailability of mometasone furoate (MF) administered from a metered‐dose inhaler containing MF and formoterol fumarate (F) (MF/F‐MDI) versus MF administered from a single‐ingredient dry‐powder inhaler (MF‐DPI).

Voriconazole, but not Posaconazole, Exposures Are Significantly Decreased by Letermovir (MK-8228) Coadministration in Healthy Subjects

Introduction: Letermovir (MK-8228) is a potent inhibitor of the cytomegalovirus (CMV) terminase complex that is being developed for the prophylaxis of CMV infection in transplant patients, who often also receive antifungal prophylaxis. The pharmacokinetics (PK) of the azole antifungals voriconazole or posaconazole were evaluated along with their tolerability when coadministered with letermovir. Materials and Methods: In the open-label, fixed-sequence trial designed to evaluate the potential effect of letermovir on the PK of voriconazole in 14 healthy female subjects, voriconazole was administered for 4 days to achieve steady state followed by 24 hours of PK sampling after the last 200 mg dose of voriconazole. The following day letermovir was dosed for 4 days alone at 480 mg daily, then, letermovir was coadministered with voriconazole for 4 days, followed again by voriconazole PK sampling. In the openlabel, fixed-sequence, 2-period, drug-drug interaction study between letermovir and posaconazole, in Period 1 an oral single dose of 300 mg of posaconazole was given to 16 healthy female subjects. In Period 2, 480 mg of letermovir was given once daily for 14 days and 300 mg of posaconazole was coadministered on Day 14. Each period was followed by PK sampling for posaconazole. Safety was monitored throughout both studies by repeated clinical and laboratory evaluations. Results: The geometric mean ratios (GMRs) for voriconazole+ letermovir/voriconazole for AUC0-12 and Cmax were 0.56 and 0.61, respectively, with corresponding 90% confidence intervals (CIs) of [0.51, 0.62] and [0.53, 0.71]. The GMRs (90% CI) for AUC0-∞ and Cmax of posaconazole when coadministered with multiple doses of letermovir were similar to that after administration of posaconazole alone with GMRs 0.98 (0.82, 1.16) and 1.11 (0.95, 1.29), respectively. When given with either voriconazole or posaconazole, letermovir was well tolerated with no severe adverse events (AEs) or discontinuations due to AEs. Conclusions: The decrease in voriconazole exposures when coadministered with letermovir may be clinically meaningful, whereas the exposures of posaconazole are unaffected by letermovir coadministration. Letermovir was well tolerated when coadministered with either posaconazole or voriconazole. 1228

Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone

To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone.

Evaluation of potential for pharmacokinetic interaction between mometasone furoate and formoterol fumarate after oral inhalation from a fixed-dose combination metered-dose inhaler device

A fixed‐dose combination (FDC) containing mometasone furoate (MF) and formoterol fumarate (F) in a pressurized metered dose inhaler (MDI) is approved for asthma and is being developed for COPD. This randomized, open‐label, 4‐period crossover study compared single‐dose pharmacokinetics of MF 800 µg; F 20 µg; MF 800 µg + F 20 µg coadministered (MF + F); and MF 800 µg/F 20 µg (MF/F) FDC in healthy subjects. MF, F, and MF + F were administered from single‐ingredient MDI devices. MF and formoterol plasma samples were obtained predose and up to 48 hours post dose for estimation of AUC0–tf (primary endpoint) and Cmax. Treatments were deemed comparable if the 90% CIs for the geometric mean ratios (GMRs) fell within 70–143%. MF AUC0–tf was comparable following treatment with MF + F versus MF (GMR 98%; 90% CI 85–113%) and MF/F versus MF + F (GMR 95%; 90% CI 82–109%). Similarly, formoterol AUC0‐tf was comparable following treatment with MF + F versus F (GMR 98%; 90% CI 77–124%) and MF/F versus MF + F (GMR 108%; 90% CI 85–136%). The 90% CIs for MF and formoterol Cmax fell within the prespecified comparability bounds for all comparisons. Systemic exposures to MF and formoterol were similar following treatment with the FDC MDI device versus individual or concomitant use of single‐ingredient MDI devices.