Once-daily T-20 is less effective than twice daily: lower potency is related to C trough

In a cross-over study, for the first two weeks of treatment, 37 patients were randomised to start T-20 plus optimised background regimen, using T-20 either once- or twice-daily for the first 7 days and switching to the alternative dose for days 8-14. Once-daily dose involved taking two 90mg doses in the morning and twice-daily doses involved each 90mg dose taken 12 hours apart. PK was measured on days 6, 7, 13 and 14. More intensive PK at steady stead was measured at 0, 1, 2, 4, 6, 8, 10, 12, 24 on days 7 and 14.

Total exposure (AUC) to T-20 and rate of clearance was similar in both schedules. While C max was approximately double when administered once-daily, C trough was also 57% lower than the BID level, and 40% of patients on the once-daily schedule had C tough levels below the target of 1.0ug/mL.

As resistance to T-20 is related to C trough, and patients using this drug are already dependent on achieving maximum response, this is a significant concern. Linear regression analysis also suggested that viral response was related to C trough and not AUC or C max. Tolerability was similar in once- and twice-daily arms.

Thompson M et al. Pharmacokinetic (PK), pharmacodynamic, and safety assessment of QD vs. BID dosing with enfuvirtide in HIV-infected subjects. 41st ICAAC, Washington, 2004. Abstract H-866.