Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin.

To investigate the effects of bosentan (Ro 47-0203), an endothelin receptor antagonist, on the pharmacokinetics and pharmacodynamics of warfarin, a double-blind, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy male volunteers. All subjects received a single oral dose of 26 mg racemic warfarin twice, once in the morning of the 6th day of treatment with 500 mg bosentan twice daily for 10 days and once at the same time point during treatment with placebo twice daily for 10 days. Both treatments were separated by a 2- to 3-week washout period. Blood samples were collected at intervals up to 120 hours following the warfarin dose for the measurement of prothrombin time and factor VII activity and for determination of plasma concentrations of R- and S-warfarin. Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC0-120 h of PT and factor VII activity compared to placebo, on average, by 23% to 38%. This reduction could be explained by an increase in the elimination of the pharmacologically more active S-enantiomer whose mean AUC0-infinity was reduced by 29%. The mean AUC0-infinity of R-warfarin was also decreased by 38%. Cmax and tmax of both enantiomers did not change. Close monitoring in patients receiving warfarin is recommended at initiation or discontinuation of treatment with bosentan.     

Multiplex analysis of genetic polymorphisms within UGT1A9, a gene involved in phase II of Δ9-THC metabolism

We present a novel multiplex assay for the simultaneous detection of 12 polymorphisms within the UGT1A9 sequence, which codes for enzymes involved in phase II biotransformation. The assay combines a multiplexed amplification step with single-base extension sequencing. The method described here is fast, cost-effective, and easy-to-use, combining the relevant features of screening methods for research and diagnostics in pharmacogenetics. To validate the assay, we tested reproducibility and sensitivity and analysed allele frequencies of 110 Caucasian individuals. Furthermore, we describe combining genetic information of individuals consuming Cannabis sativa products with respective plasma concentrations of a metabolite.

     

Risk and protective factors for sexual risk taking among adolescents involved in Prime Time

This article describes a preliminary qualitative evaluation of risk and protective factors associated with consistent contraceptive use and healthy sexual decision-making among ten of the first participants in the Prime Time intervention study. Prime Time is an 18-month intervention including one-on-one case management and peer educator training targeting sexually active 13-17-year-old girls who are recruited from health care clinics. Using an approach grounded in findings from previous research, social cognitive theory, and the social development model, Prime Time aims to improve participants' contraceptive use consistency, reduce number of sexual partners, and reduce unwanted sexual activity. Findings from this preliminary evaluation alert health care providers to the complex and dynamic nature of adolescent girls' sexual behaviors and to a broad range of risk and protective factors within individuals and their environments that may influence adolescent girls' sexual behaviors and contraceptive use. Findings suggest that an ongoing, supportive relationship with a case manager who is able to pace and tailor an intervention to the individual young person can have positive effects on adolescent girls' sexual behaviors and contraceptive use.     

Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients

PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.     

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects     

Cost Utility of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease

Objective

The gene therapy voretigene neparvovec (VN) is the first Food and Drug Administration–approved treatment for vision loss owing to the ultra-rare RPE65-mediated inherited retinal disorders. We modeled the cost-utility of VN compared with standard of care (SoC).

Impact of Abuse Deterrent Formulations of Opioids in Patients With Chronic Pain in the United States: A Cost-Effectiveness Model

Objective

Opioid abuse is a significant public health problem in the United States. We evaluate the clinical effectiveness and economic impact of abuse-deterrent formulations (ADF) of opioids relative to non-ADF opioids in preventing abuse.

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.