Effect of steady-state faldaprevir on the pharmacokinetics of steady-state methadone and buprenorphine-naloxone in subjects receiving stable addiction management therapy.

The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC(0-24,ss)), the steady-state maximum concentration of the drug in plasma (C(max,ss)), and the steady-state concentration of the drug in plasma at 24 h (C(24,ss)) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.).

Clinical assessment of potential drug interactions of faldaprevir, a hepatitis C virus protease inhibitor, with darunavir/ritonavir, efavirenz, and tenofovir.

BACKGROUND: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients. METHODS: In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated. RESULTS: Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined. CONCLUSIONS: No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).

Pharmacokinetics and pharmacodynamics of the antiplatelet combination aspirin (acetylsalicylic acid) plus extended-release dipyridamole are not altered by coadministration with the potent CYP2C19 inhibitor omeprazole.

BACKGROUND: The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA+ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA+ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted. OBJECTIVE: This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA+ER-DP. STUDY DESIGN AND SETTING: This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit. PARTICIPANTS: Sixty healthy male and female volunteers aged 18-50 years were included in the study. INTERVENTION: Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of ≥14 days between the second and third treatments. Treatment A=ASA+ER-DP 25 mg/200 mg (Aggrenox®) twice daily (BID) alone; B=ASA+ER-DP 25 mg/200 mg BID+omeprazole (Prilosec®) 80 mg once daily (QD) following ASA+ER-DP alone for 7 days; C=omeprazole 80 mg QD alone; D=omeprazole 80 mg QD+ASA+ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days. MAIN OUTCOME MEASURES: The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation. RESULTS: Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC0-12,ss, ng·h/mL) and maximum plasma concentration (Cmax,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90% confidence interval [CI] 90.96-102.13) for AUC0-12,ss and 92.03 (86.95-97.40) for Cmax,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32-99.72) at 4 h after last dose. All treatments were well tolerated. CONCLUSION: The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.

Sexual desire problems in women seeking healthcare: a novel study design for ascertaining prevalence of hypoactive sexual desire disorder in clinic-based samples of U.S. women.

BACKGROUND: Hypoactive sexual desire disorder (HSDD) has been estimated to occur in 10%-15% of adult women in large population-representative and community-based studies. However, none of these studies have used in-person diagnostic interview assessment to rule out alternative diagnoses, nor has the impact of other health conditions or help-seeking experiences been investigated. The current study aimed to determine the prevalence of generalized acquired HSDD in women aged ≥18 who attended primary care or obstetrics and gynecology clinics for nonurgent clinic visits in the United States. METHODS: A total of 701 women were enrolled at 20 clinical sites across the United States between June 11, 2010, and October 15, 2010. Participants completed a two-part self-administered questionnaire, and a validated, structured, in-person diagnostic interview, conducted by a trained health professional was used for diagnosing HSDD according to DSM-IV-TR criteria. RESULTS: Fifty-two women (7.4%) were assigned a diagnosis of generalized acquired HSDD. Prevalence was lower in minority and postmenopausal women. Level of education and other sociodemographic factors did not appear to differentiate between women with and without HSDD. A marked increase in HSDD prevalence was noted in the perimenopausal (i.e., 40-49 years) and immediate postmenopausal (i.e., 50-59) age groups. Of the women diagnosed with HSDD, 53% had sought care from a health professional for HSDD. CONCLUSIONS: In this sample of women recruited in the clinical care setting, we observed an overall prevalence rate of 7.4% of acquired, generalized HSDD, with markedly increased prevalence in midlife women.