Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers.

OBJECTIVE: Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS: Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS: The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS: These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.

Treatment of defecation disorders by colonic enemas in children with spina bifida.

Faecal incontinence and constipation are well known problems in children with spina bifida. Effective treatment can be difficult and this gave the condition a low priority despite the obvious physical and psychological sequelae. Positive experience with colonic enemas (CE) in the paediatric post-operative care have led us to adopt this method as the treatment of choice for defecation disorders in children with spina bifida. In 41 spina bifida children (mean age 8.4 years, range 7 months to 22 years), retrograde CEs with hand-warm tap water were given at home from once a day to twice per week. Satisfaction with the procedure was evaluated with a questionnaire sent out after a mean follow-up period of 33 months (range 6 to 55 months). The indications to start CEs were faecal incontinence (27%), constipation (27%) or both. 34% of 41 children also had other gastrointestinal complaints, 7% had headaches, 29% had poor appetite and 15% felt generally unwell. Before the start of CE 22% of the children had been on a diet, 37% on oral laxatives, 31% on a rectal laxative and 44% had to have manual evacuations. 90% used diapers on a daily basis. At the end of the follow-up period 27% of the children were still on a diet and 17% still used oral laxatives but rectal laxatives were no longer used nor were manual evacuations necessary. 66% of the 41 children were completely faecally continent and constipation occurred only occasionally, no child had faecal retention or impaction. At follow-up 39% still used diapers regularly and 20% used a panty-line and complaints of abdominal pain, headache and poor appetite were rare. Satisfaction with the procedure was rated highly by 63% of parents and children and good by 37% but 15% of the children found regular CEs painful. It is concluded from the study that CEs are therapeutically effective in the treatment of both faecal incontinence and constipation in children with spina bifida. The procedure is well tolerated even by very young children. Long-term histopathological effects of daily CEs on the lower gastrointestinal tract needs to be evaluated by future research.