HIV AIDS News [International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

Relationships between indinavir (IDV) pharmacokinetics and antiviral activity in phase I/II
trials [Abstract #42266]
12th World AIDS Conference
June 28 - July 3, 1998
Geneva, Switzerland
Jeffrey Chodakewitz, P. Deutsch, R. Leavitt, J. McCrea, M. Nessly, A. Sterrett, G. Winchell
Merck Research Laboratories, West Point Pennsylvania, USA
Background: The antiviral activity of indinavir has been clearly demonstrated to be dosedependent in early dose-finding studies at doses between 0.8 g/day to 2.4 g/day. In this
analysis, we investigate the existence of a relationship between antiviral activity and individual
pharmacokinetic (PK) data at doses of 1.8-3.2 g/day, closer to the therapeutic dose range.
Methods: Data were pooled from all patients treated with IDV monotherapy in Phase I and
Phase II clinical protocols for which there were measurements of both serum viral RNA decline
at weeks 4 and/or 24 and plasma PK at steady state. Total daily IDV dose ranged from 1.8
g/day to 3.2 g/day, given q8h or q6h. There were 95 patients eligible for analyses from Merck
sponsored protocols. The majority (75/95) were receiving IDV at doses >=2.4 g/day. Viral RNA
(vRNA) at baseline ranged from 13,000 to 649,840 copies/mL (median 74,320 copies/mL).
Results: There was no statistically significant correlation between vRNA decline (week 4 or 24)
and either daily AUC (AUC over one dosing interval [times] doses per day) or C_{trough}. All
correlation coefficients were between -0.15 and +0.1, and p values >=0.15. Daily AUC and
C_ {trough} values were not distinguishable between the groups with vRNA >= 500 copies/mL
versus <500 copies/mL.
Conclusions: Near the therapeutic dose range, the poor correlation of antiviral activity and PK
suggests that factors other than PK play important roles in inter-patient variability in response.
Intra-patient variability in plasma PK may also obscure small correlations. Additional
investigations for correlations are warranted, but available data do not identify relevant PK
target values to guide dose modifications for individual patients on therapeutic doses of
indinavir.