Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.
OBJECTIVE
The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level.


METHODS
Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT).


RESULTS
In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L.


CONCLUSIONS
Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.
Cheng
C L
CL
College of Pharmacy, Upjohn Center for Clinical Pharmacology, University of Michigan, Ann Arbor 48109-0504, USA.
Smith
D E
DE
Carver
P L
PL
Cox
S R
SR
Watkins
P B
PB
Blake
D S
DS
Kauffman
C A
CA
Meyer
K M
KM
Amidon
G L
GL
Stetson
P L
PL
D000284:Administration, Oral; D000328:Adult; D000478:Alkylation; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D020008:Delavirdine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004917:Erythromycin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D006679:HIV Seropositivity / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013379:Substrate Specificity
D019380:Anti-HIV Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D010879:Piperazines; D011500:Protein Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004917:Erythromycin; D020008:Delavirdine; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating