Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study.
OBJECTIVE
The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes.


METHODS
Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV-RNA.


RESULTS
Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log10 changes in HIV-RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA]7/[TA]7 genotypes. No relationships were identified with BCRP.


CONCLUSIONS
Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.
Anderson
Peter L
PL
University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
Lamba
Jatinder
J
Aquilante
Christina L
CL
Schuetz
Erin
E
Fletcher
Courtney V
CV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D017931:DNA Primers; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000627:therapeutic use*; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010597:Pharmacogenetics; D010865:Pilot Projects; D012189:Retrospective Studies; D012269:Ribosomal Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use*; D001741:Black or African American
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; D017931:DNA Primers; D019469:Indinavir; D019259:Lamivudine; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D015215:Zidovudine; C073492:ABCC4 protein, human; C093947:MRP2 protein, S cerevisiae