The Association between Cigarette Smoking and Efavirenz Plasma
Concentration using the Population Pharmacokinetic Approach
Abstract
Aim: Efavirenz is still widely used as the preferred first-line
antiretroviral agent in the middle- and low- income countries, including
Malaysia. The efavirenz population pharmacokinetic profile among
HIV-positive smokers is still unknown. We aimed to assess the
association of smoking with efavirenz and the differences in HIV
clinical outcomes. Methods: A total of 154 stable HIV-positive patients
on efavirenz in northern Malaysia were recruited with a sparse sampling
for this multicentre prospective cohort study. The association between
smoking and efavirenz pharmacokinetic parameters was determined using
the non-linear mixed-effect model (NONMEM). A mixture model of clearance
was adopted to describe the metaboliser status because genetic data is
unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 /
CD8 ratio and viral blips) for at least two years after the
antiretroviral initiation was also investigated. Results: Our data were
best fitted with a one-compartment mixture model with first-order
absorption without lag time. Smoking significantly associated with
higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07
to 1.91), while weight affected both CL/F and volume (V/F). From the
mixture model, 20% of patients were in the slow clearance group, which
mimic the genotype distribution of slow metaboliser. An efavirenz dose
reduction is not recommended for smokers ≥60kg with normal metabolism
rate. Smoking significantly associated with slower normalisation of CD4
and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with
significantly higher efavirenz clearance and unfavourable clinical
outcomes. Close monitoring of adherence and clinical response among
smokers is warranted.