1575A 28-day high-dose safety and pharmacokinetics study of raltegravir in healthy subjects

Background. ISENTRESS (raltegravir, RAL) is licensed for 400 mg b.i.d. use. An investigational 1200 mg q.d. regimen for reformulated raltegravir (re-RAL) is under clinical development. This study assessed the safety and pharmacokinetics (PK) of a higher dose of re-RAL. Methods. A double-blind, multiple-dose, randomized, fully domiciled study assessed the safety and PK of 1800 mg dose of re-RAL tablets (n = 18) or matching placebo (n = 6), given q.d. for 28 days in healthy subjects (18 to 55 years). Results. There were no deaths and no serious adverse events. There were no clinically significant findings for vital signs or ECG data. A total of 23 subjects (95.8%) reported an adverse event (AE) that was related to the study drug [17 subjects (94.4%) after 1800 mg re-RAL and 6 subjects (100%) after matched placebo]. Two subjects withdrew their consent at Day 28 for personal reasons. No subjects discontinued the study due to AEs or changes in laboratory safety. Most common adverse events, reported in ≥6 subjects, included headache, myalgia, and abdominal pain. No subjects experienced ALT >5x upper limit of normal (ULN) in this study. One subject experienced ALT >3x ULN on Day 9 and another subject experienced ALT >2x ULN on Day 13, after 1800 mg re-RAL administration. No associated clinically significant symptoms were seen and the elevations stabilized or returned to normal without interruption of study therapy. Three subjects experienced CPK elevations which were rated severe in intensity and were considered related to the study drug. In two subjects, the first CPK elevations were detected at the post study visit held 2-weeks following completion of the dosing. While one subject showed asymptomatic increase in CPK level, CPK elevations in two subjects were symptomatic. RAL PK was comparable on Days 14 and 28. On Day 28, the mean values of RAL Cmax, C24hr, and AUC0-24hr were 29 μM, 88.5 nM, 74.5 hr. μM, respectively, as compared with 20.6 μM, 81.1 nM, and 59.5 hr.μM, respectively, at the 1200 mg dose being evaluated in Phase 3. There were no apparent relationship between PK and observed elevations in ALT or CPK. Conclusion. Administration of 1800 mg q.d. doses of re-RAL was safe and well tolerated. Data from this study, in combination with other recently completed Phase I studies, support the continued development of the q.d. dosing regimen. Disclosures. R. Krishna, Merck and Co.: Employee, Salary M. Rizk, Merck and Co., Inc.: Employee, Salary V. Schulz, Merck and Co., Inc.: Employee, Salary J. Bruggencate-Broeders, Merck and Co.: Employee, Salary R. Liu, Merck and Co: Employee, Salary P. Larson, Merck and Co.: Employee, Salary K. Abou-Farha, Merck and Co., Inc.: Investigator, Investigator for Merck Study