Drug interaction reports from Liverpool University website

30 October 2008. Related: PK and drug interactions.

High incidence of side effects when rifampicin used with adjusted doses of lopinavir/ritonavir tablets

A study has shown a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets (either 600/150 or 800/200 mg twice daily) was combined with rifampicin (600 mg once daily).

The study was terminated prematurely when only 11/40 subjects had been given both drugs. 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 HIV+ patients.

Ref: Nijland HM et al. High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets. AIDS, 2008, 22(8): 931-935.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=372

Ketoconazole and darunavir interaction with and without ritonavir

The aim of this study was to investigate the interaction between ketoconazole and darunavir alone nd in combination with low-dose ritonavir), in HIV-healthy volunteers. Volunteers received darunavir (400 mg twice daily) alone and plus ketoconazole (200 mg twice daily) in two sessions (Panel 1), or darunavir/ritonavir (400/100 mg twice daily), ketoconazole (200 mg twice daily) and darunavir/ritonavir/ketoconazole (400/100/200 mg twice daily) over three sessions (Panel 2). Treatments were administered with food for 6 days and steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments.

During darunavir and ketoconazole co-administration, darunavir AUC12h increased by 155% (90% CI 80, 261), compared with treatment with darunavir alone. Darunavir AUC12h increased by 42% (90% CI 23, 65) during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole AUC was unchanged by coadministration with darunavir alone, but increased by 212% (90% CI 165, 268), during co-administration with darunavir/ritonavir compared with ketoconazole alone.

The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg/day is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.

Reference:

Sekar VJ et al. Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers. Br J Clin Pharmacol, 2008, Epub ahead of print.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=373

Webcast – Presentation on “Predicting, Avoiding, and Managing Drug Interactions”.

At the IAS-USA regional 1-day, advanced-level CME courses on HIV/AIDS-related treatment issues meeting in Atlanta in February, Prof David Back gave a presentation on drug interactions, followed by a question and answer session – both of these are now available as webcasts.

http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=376

Review: Detecting herbal interactions

Drug interactions with herbal preparations generate great interest, but few pharmacokinetic data. This review looks at ways of predicting herb-drug interactions and focuses on pharmacokinetic profiling.

It starts by discussing the mechanisms of interactions, covering cytochrome P450 inhibition and induction, as well as transporter based mechanisms. It then moves on to experimental methods for assessing interactions and highlights problems with some in vitro techniques. Finally it looks at how to determine the clinical relevance of interactions.

The review gives an insight into the problems of conducting studies with herbal preparations (for example standardising active components, species differences, pitfalls of the cocktail approach) and gives examples of how it can be difficult to extrapolate in vitro findings to the clinical situation.

Ref: Derendorf H. Potential of pharmacokinetic profiling for detecting herbal interactions with drugs. Butterweck V, Clin Pharmacokinet, 2008, 47(6): 383-397. http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=375

Drug Interactions: Lamotrigine and atazanavir or atazanavir/ritonavir

The emergence of novel interactions involving anti-HIV therapy is a constant reminder that the treatment of HIV+ patients with co-morbidities is complex and challenging. Atazanavir boosted with ritonavir is a preferred protease inhibitor combination for treatment naive patients, but here the interaction with the antiepileptic drug lamotrigine is likely to be clinically relevant. HIV- subjects (n=17) received single doses of lamotrigine (100 mg) with atazanavir alone (400 mg once daily) or atazanavir/ritonavir (300/100 mg once daily). Lamotrigine AUC decreased by 12% in the presence of atazanavir and by 32% in the presence of atazanavir/ritonavir.

The decrease in lamotrigine exposure was due to increased formation of the 2N-glucuronide in the presence of ritonavir. Unlike atazanavir alone which inhibits UGT1A1, the ritonavir component is an inducer of UCG1A4. Other UGT1A4 substrates likely to be affected by this interaction include clozapine, olanzapine and tamoxifen.

Reference:

Burger DM, Huisman A, Van Ewijk N, et al. The effect of atazanavir and atazanavir/ritonavir on UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe. Clin Pharmacol Ther, 2008, Epub ahead of print.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=375