Increasing Nevirapine Dose Can Overcome Reduced Bioavailability Due to Rifampicin Coadministration

Abstract

We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 microg/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 microg/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

“…In our study, rifampicin induced the metabolism of nevirapine, seen as an increase in its CL/F by 37.4%, which is in agreement with previous reports of rifampicin altering the pharmacokinetics of nevirapine [4,9,10,12,13]. This may be due to the induction of CYP3A4 and CYP2B6 leading to an enhancement of nevirapine metabolism.…”

“…The mutation is observed after 4 weeks of monotherapy and may occur in just 2 weeks if viral replication is not well controlled in the presence of nevirapine [4]. Several reports on the effect of rifampicin on nevirapine pharmacokinetics have been published [4,[9][10][11][12][13][14]. However, to our knowledge this is the first modelling report on the effect of rifampicin on nevirapine pharmacokinetics in South African patients.…”

“…In another group of 13 HIV-infected patients, rifampicin reduced the nevirapine AUC by 46%, the C max by 42% and the C min by 53%, and in eight of the 13 patients the C min was below 3 mg/L. Increasing the nevirapine dose to 300 mg twice daily elevated C min above 3 mg/L [9]. Co-administration of nevirapine and rifampicin in five patients coinfected with HIV and TB led to a significant reduction in nevirapine AUC 0-12 (by 31%) and C max (by 36%) [10], but there was no significant decrease in C min .…”

Clinical Relevance of Drug Interactions in HIV-Infected Patients Receiving Antiretroviral Therapy

“…This combination is considered absolutely contraindicated McCance-Katz et al, 2006;Matteelli et al, 2007a;Ramachandran et al, 2006;Ribera et al, 2001) Delavirdine (Borin et al, 1997;DeJong et al 2004;McCance-Katz et al, 2006;Spradling et al, 2002) Nevirapine (Benator et al, 2007;Blumberg et al, 2003;Borin et al, 1997;Burger et al, 2006;Hamzeh et al, 2003;Kraft et al, 2004;La Porte et al, 2004;Polk et al, 2001;Ramachandran et al, 2006;Ribera et al, 2001Ribera et al, , 2007Rolla et al, 2006) 2: high risk 3: medium risk…”

“…(DHSS, 2011) Rifampicin and NNRTI. (Finch et al, 2002;de Jong et al, 2004;Ribera et al, 2001;Ramachandran et al, 2006;Weiner et al, 2005) In general, the use of rifampicin together with delavirdine is considered contraindicated (Borin et al, 1997) (level 1: very high risk).…”