Nevirapine Once Daily Versus Twice Daily: implications for drug-drug interactions

Nevirapine Once Daily Reduced Methadone Levels by 30% Compared to Taking Nevirapine Twice Daily.

Kristel Crommentuyn and colleagues from the Slotervaart Hospital in Amsterdam, the Netherlands reported on how once daily 400 mg nevirapine (NVP) may cause drug interactions not caused by using NVP twice daily 200 mg (abstract 1.11). The authors gave background by describing how a 44 yr old female was receiving 15 mg daily of methadone for opoid abuse. When her ART regimen was changed from d4T (40mg bid) + 3TC (150 mg bid) + indinavir (1400 mg bid) to d4T+3TC + NVP 200 mg bid, the methadone dose had to be increased to 30 mg daily because symptoms of methadone withdrawal occurred. Methadone is metabolized by the CYP3A4 isoenzyme so the need to increase methadone dose can be explained by the effect of NVP of inducing the metabolizing of methadone, that methadone metabolism was increased and excreted or cleared more quickly. So higher methadone doses were needed. Several other studies have shown that NVP and Sustiva have this effect on methadone.

At a future time the patient received NVP 400 mg once daily in a 14-day bioequivalence study, and she started experiencing methadone withdrawal. So her methadone dose was increased to 40 mg daily. To determine whether the symptoms of withdrawal were caused by decreased plasma levels of methadone, the concentrations were measured by TDx-FLx. The AUC of methadone was decreased by about 30% with NVP 400 mg once daily compared to NVP 200 mg twice daily. After the NVP dose was changed back to 200 mg bid, the symptoms of withdrawal disappeared. The authors suggested this experience may have been due to differences in induction of the CYP3A4 isoenzymes by NVP between once daily and twice daily NVP dosing. In other words, once daily dosing of NVP may change metabolism of other drugs compared to twice daily NVP dosing. Therefore, the authors started this study to evaluate the effect of NVP 200 mg bid and 400 mg QD on the exposure or blood levels of protease inhibitors which are also processed by CYP3A4.

Patients were randomized to either 400 mg QD or 200 mg bid NVP as part of a HAART regimen. 14 days later plasma samples were collected to assess the pharmacokinetics profile of NVP in plasma during a 24 hour period. At day 15, the patients were switched to the alternate dosing regimen. At day 29 blood sampling was repeated. After an overnite fast NVP was ingested with water. Concurrent medication was ingested 1.5 hours after ingestion of NVP during breakfast. If indinavir was used this drug was ingested together with NVP. If ddI was used, this drug was ingested 1 hour before ingestion of NVP. Five-ml venous blood samples were collected in heparinised tubes just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after ingestion of NVP. For the once daily regimen additional samples were drawn at 14, 16 and 24 hours post ingestion of NVP. The protease inhibitors were quantified simultaneously using a sensitive, validated, isocratic reversed-phase high-performance liquid chromatographic assay with UV detection.

RESULTS

8 patients in the bioequivalence study from which these patients were taken were using protease inhibitors concomitantly. 6 patients used IDV, RTV or SQV. A decrease in the AUC (total drug blood level during the dosing period) during the dosing interval of the protease inhibitors with NVP 400 mg QD vs 200 mg bid was observed. The median decrease in the PI concentration at the end of the dosing period was 31.4% for the QD compared to the bid dosing. The exposure to NVP (AUC-24h) was not significantly different between the NVP QD and bid dosing. The Cmax (peak drug level) was higher in the qd vs the bid dosing. However, no relationship between the Cmax of NVP and the PI levels could be seen. However, based on my perception of the % reduction in AUC the clinical significance needs to be further researched. For example, in 1 patient taking IDV 800 mg tid, the % difference in AUC was –16.2% for the qd vs bid dose. For the patient taking IDV 1400 mg bid the AUC reduction was –29.7%. For the patient taking IDV 800 mg bid + RTV 100 mg bid the reduction was 15% for the IDV and 38% for the RTV. For a patient taking 600 mg RTV bid, the reduction in AUC was –1.6%. For the patient taking RTV 400 mg bid+SQV 400 mg bid the RTV was reduced 16.8% and the SQV was reduced 51%.

Conflicting results were seen for NFV. As NFV is metabolized not only by CYP3A4, but also by CYP2C19, CYP2C9, and CYP2D6, the effect of inhibition of CYP3A4 by NVP might be less distinct. RTV, IDV and SQV are metabolized primarily by CYP3A4 making them more susceptible to the inductive capacity of NVP. For the patient taking NFV 1000 mg bid the % difference in AUC was –5.0% compared to the bid dose, while for the patient taking NFV 1500 mg bid the % difference in NFV AUC was +97% compared to the bid dose.

1 of the 8 patients was taking RTV 800 mg bid + 400 mg SQV bid and the AUCs of these drugs were not reduced by NVP qd vs bid but were slightly increased, although the increase may not be significant. Still, not many persons are taking this dosing regimen. A second patient was taking 400/400 RTV/SQV bid and their RTV and SQV AUCs were reduced. The authors concluded that a change in NVP dosing to 400 mg once daily vs 200 mg twice daily may affect the exposure to protease inhibitors taken simultaneously. The mechanisms and clinical implications need further investigation.