Phase 1 study of combination therapy with L-697,661 and zidovudine. The ACTG 184 Protocol Team.
We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen.
Schooley
R T
RT
University of Colorado Health Sciences Center, Denver 80262, USA.
Campbell
T B
TB
Kuritzkes
D R
DR
Blaschke
T
T
Stein
D S
DS
Rosandich
M E
ME
Phair
J
J
Pottage
J C
JC
Messari
F
F
Collier
A
A
Kahn
J
J
D000328:Adult; D000983:Antipyrine; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001583:Benzoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018592:Cross-Over Studies; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000737:chemistry; D004347:Drug Interactions; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D015751:Genes, pol / Q000235:genetics; D005838:Genotype; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010865:Pilot Projects; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000998:Antiviral Agents; D001583:Benzoxazoles; D017931:DNA Primers; D004279:DNA, Viral; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076516:L-697661; D015215:Zidovudine; D000983:Antipyrine