Background: The initial 50 mg/mL T-20 carbonate (CO3) formulation required 2 injections BID to deliver a dose of 90 mg BID. High-strength (100 mg/mL) CO3 and TRIS formulations have been developed to reduce the number of daily injections.

Methods: This sequential, cross-over study compared the initial T-20 50 mg/mL CO3 formulation (100 mg BID, 90 mg deliverable) to a T-20 100 mg/mL CO3 formulation (75 mg, 67.5 mg deliverable; and 100 mg BID, 90 mg deliverable) and a 100 mg/mL TRIS formulation (100 mg BID, 90 mg deliverable). All patients received active ARV therapy in addition to T-20. A 28-day steady-state cross-over phase (from high-strength formulations to 50 mg/mL CO3) evaluated pharmacokinetics and tolerability. Afterwards, safety, tolerability, and antiviral activity of the high strength T-20 CO3 and TRIS formulations were observed for 48 weeks. The study was not designed to discriminate among cohorts.

Results:  46 triple-class, treatment-experienced patients participated: 22 in the 100 mg/mL 90 mg BID CO3 cohort, 12 in the 100 mg/mL 67.5 mg BID CO3 cohort, and 12 in the 100 mg/mL 90 mg BID TRIS cohort. The median baseline HIV-1 RNA was 5.37 log₁₀ C/mL, and median CD4+ cell count was 24 cells/mm³. Only 3 (6.5%) patients discontinued before week 48. Pharmacokinetic analysis indicated that the 50 mg/mL and 100 mg/mL CO3 formulations were bioequivalent.  Injection site reactions (ISR) were the most frequent adverse event; all patients experienced at least 1 event, but none discontinued the study due to an ISR. All signs/symptoms occurred more frequently in patients in the TRIS cohort. During the 28-day pharmacokinetic phase, there was a tendency for the severity of ISRs to lessen when patients switched from TRIS to 50 mg/mL CO3 formulations. Besides ISRs, diarrhea, nausea, lymphadenopathy, and nasopharyngitis were the most common AEs. Activity results were:

 

Median (ITT) Week 48 Activity
	100 mg/mL CO3 100 mg BID N = 22	100 mg/mL CO3 75 mg BID N = 12	100 mg/mL TRIS 100 mg BID N = 12
< 400 C/mL (%)	59	67	17
Log10 change BL	-2.97	-3.48	-0.87
Viral Failure (%)	23	17	58
CD4+ change BL	111	175	79

Conclusions:

The 50 mg/mL and 100 mg/mL CO3 formulations of T-20 were bioequivalent. Although all patients experienced ISRs, no patient discontinued due to ISR. The overall safety profile appeared similar between the 100 mg/mL CO3 and TRIS formulations through 48 weeks. The pharmacokinetics, safety, and activity of T-20 in the 100 mg/mL CO3 formulation support its development in Phase III trials at 2 injections per day.