Limited sampling models to predict the pharmacokinetics of nevirapine, stavudine, and lamivudine in HIV-infected children treated with pediatric fixed-dose combination tablets.

Full 12-hour pharmacokinetic profiles of nevirapine, stavudine, and lamivudine in HIV-infected children taking fixed-dose combination antiretroviral tablets have been reported previously by us. Further studies with these formulations could benefit from less-intensive pharmacokinetic sampling. Data from 65 African children were used to relate area under the plasma concentration versus time curve over 12 hours (AUC) to plasma concentrations of nevirapine, stavudine, or lamivudine at times t = 0, 1, 2, 4, 6, 8, and 12 hours after intake using linear regression. Limited sampling models were developed using leave-one-out crossvalidation. The predictive performance of each model was evaluated using the mean relative prediction error (mpe%) as an indicator of bias and the root mean squared relative prediction error (rmse%) as a measure of precision. A priori set criteria to accept a limited sampling model were: 95% confidence limit of the mpe% should include 0, rmse% less than 10%, a high correlation coefficient, and as few (convenient) samples as possible. Using only one sample did not lead to acceptable AUC predictions for stavudine or lamivudine, although the 6-hour sample was acceptable for nevirapine (mpe%: -0.8%, 95% confidence interval: -2.2 to +0.6); rmse%: 5.8%; r: 0.98). Using two samples, AUC predictions for stavudine and lamivudine improved considerably but did not meet the predefined acceptance criteria. Using three samples (1, 2, 6 hours), an accurate and precise limited sampling model for stavudine AUC (mpe%: -0.6%, 95% confidence interval: -2.2 to +1.0; rmse%: 6.5%; r: 0.98) and lamivudine AUC (mpe%: -0.3%, 95% confidence interval: -1.7 to +1.1; rmse%: 5.6%; r: 0.99) was found; this model was also highly accurate and precise for nevirapine AUC (mpe%: -0.2%, 95% confidence interval: -1.0 to +0.7; rmse%: 3.4%; r: 0.99). A limited sampling model using three time points (1, 2, 6 hours) can be used to predict nevirapine, stavudine, and lamivudine AUC accurately and precisely in HIV-infected African children

Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets.

OBJECTIVE: Triomune Baby and Junior have been developed in response to the urgent need for appropriate paediatric fixed-dose combination antiretroviral tablets, with higher nevirapine to stavudine and lamivudine ratios than adult tablets, in accordance with paediatric recommendations. We determined whether this ratio results in optimal exposure in the target population. METHODS: Seventy-one Zambian children were treated with Triomune Baby or Junior dosed according to weight bands. After 4 weeks or more, a 12-h pharmacokinetic curve was recorded. Antiretroviral plasma concentrations were assayed by high-performance liquid chromatography. RESULTS: Six children were excluded because of poor adherence. Of the remaining 65, 24 (37%) were female, 24 (37%) weighed less than 15 kg and most were malnourished. Mean (range) nevirapine C12h, Cmax and AUC12h of 6.0 (1.4, 16.9) mg/l, 10.0 (3.8, 22.5) mg/l and 94.4 (32.1, 232) mg/l per hour were higher than those reported in adults. Nevirapine C12h was subtherapeutic (< 3.0 mg/l) in four children (6%). Mean stavudine and lamivudine C12h, Cmax, AUC12h (< 0.015 mg/l, 0.45 mg/l, 1.05 mg/l per hour and 0.09 mg/l, 1.33 mg/l, 5.42 mg/l per hour) were comparable to adults. There was no evidence of a difference in nevirapine AUC12h across weight bands (P = 0.2), whereas the difference in stavudine (P = 0.0003) and lamivudine AUC12h (P = 0.01) was driven by the single weight band with unequal dosing. CONCLUSION: Nevirapine concentrations were higher but more variable than in adults; the pharmacokinetic parameters of stavudine and lamivudine were comparable to adults. As nevirapine underdosing is of greater concern than overdosing, the Triomune Baby and Junior ratio appears to be appropriate for children weighing 6 kg and over. Further research is required for children under 6 kg

High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets.

Contains fulltext : 70023.pdf (publisher's version ) (Closed access)OBJECTIVE: Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced lopinavir/ritonavir tablets. METHODS: A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period. RESULTS: Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks. CONCLUSIONS: The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients