Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: A pilot study

Peter L. Anderson, Jatinder Lamba, Christina L. Aquilante, Erin Schuetz, Courtney V. Fletcher

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

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. STUDY DESIGN: 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. DISCUSSION: 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.

Original languageEnglish (US)
Pages (from-to)441-449
Number of pages9
JournalJournal of Acquired Immune Deficiency Syndromes
Volume42
Issue number4
DOIs
StatePublished - Aug 1 2006

Fingerprint

Indinavir
Lamivudine
Zidovudine
Pharmacogenetics
HIV
Cytochrome P-450 CYP3A
Therapeutics
RNA
Drug Utilization
Heterozygote
Bilirubin
Pharmaceutical Preparations
African Americans
Pharmacokinetics
Genotype
Pharmacology

Keywords

  • Antiretroviral therapy
  • Clinical pharmacology
  • HIV/AIDS
  • Pharmacodynamics
  • Pharmacogenetics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults : A pilot study. / Anderson, Peter L.; Lamba, Jatinder; Aquilante, Christina L.; Schuetz, Erin; Fletcher, Courtney V.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 42, No. 4, 01.08.2006, p. 441-449.

Research output: Contribution to journalArticle

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AU - Anderson, Peter L.

AU - Lamba, Jatinder

AU - Aquilante, Christina L.

AU - Schuetz, Erin

AU - Fletcher, Courtney V.

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AB - 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. STUDY DESIGN: 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. DISCUSSION: 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.

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