Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication.

BACKGROUND The aim of this study was to examine factors influencing plasma concentration of efavirenz and nevirapine. METHODS Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake. RESULTS Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). Notably, without adjustment for other factors, patients on rifampicin had 48% higher efavirenz concentration, as these patients were mostly black and on 800 mg/day. For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024). CONCLUSIONS We observed clear associations between ethnicity and concentrations of nevirapine and efavirenz. Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine; however, for efavirenz this effect was more than counterbalanced by the effect of ethnicity and increased efavirenz dose. There was also an additional impact of weight, which should be considered when determining optimal dosage. Other associations from our analysis (between tenofovir or protease inhibitor and nevirapine, and zidovudine and efavirenz), require confirmation in formal pharmacokinetic studies.