Nonnucleoside reverse transcriptase inhibitor pharmacokinetics in a large unselected cohort of HIV-infected women.
BACKGROUND
Small intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogenous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside reverse transcriptase inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response.


METHODS
Two hundred twenty-five women on NNRTI-based antiretroviral regimens from the Women's Interagency HIV Study were enrolled into 12-hour or 24-hour PK studies. Extensive demographic, laboratory, and medication covariate data were collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area under the concentration-time curves.


RESULTS
Hepatic inflammation and renal insufficiency were independently associated with increased nevirapine exposure in multivariate analysis: crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n = 106). Higher efavirenz exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African American, and amenorrhea were associated with decreased exposure (n = 119). With every 10-fold increase in nevirapine or efavirenz exposure, participants were 3.3 and 3.6 times likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy.


CONCLUSIONS
Our study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the "real-world" setting. Comprehensive PK studies in representative populations are feasible and may ultimately lead to dose optimization strategies in patients at risk for failure or adverse events.
Gandhi
Monica
M
Department of Medicine, University of California San Francisco, 405 Irving Street, 2nd floor, San Francisco, CA, USA. monica.gandhi@ucsf.edu
Benet
Leslie Z
LZ
Bacchetti
Peter
P
Kalinowski
Ann
A
Anastos
Kathryn
K
Wolfe
Alan R
AR
Young
Mary
M
Cohen
Mardge
M
Minkoff
Howard
H
Gange
Stephen J
SJ
Greenblatt
Ruth M
RM
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D048588:Benzoxazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015331:Cohort Studies; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D015999:Multivariate Analysis; D019829:Nevirapine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz