Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes.
BACKGROUND
Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.


METHODS
In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.


RESULTS
EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.


CONCLUSIONS
Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda ; CIHR, Canadian HIV Trials Network, Vancouver, British Columbia, Canada.
Jackson K
JK
Mukonzo
School of Pharmacy, Union University, Jackson, Tennessee, United States of America.
Joel S
JS
Owen
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.
Jasper
J
Ogwal-Okeng
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.
Ronald B
RB
Kuteesa
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.
Sarah
S
Nanzigu
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.
Nelson
N
Sewankambo
Departments of Clinical Epidemiology and Biostatistics, Pediatrics and Anaesthesia, McMaster University, Hamilton, Ontario, Canada ; Biostatistics Unit, St. Joseph's Healthcare-Hamilton, Hamilton, Ontario, Canada.
Lehana
L
Thabane
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
Lars L
LL
Gustafsson
Division of Translational Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
Colin
C
Ross
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska Institutet, Stockholm, Sweden.
Eleni
E
Aklillu
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010597:Pharmacogenetics; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D014454:Uganda; D015215:Zidovudine / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz