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  14th International Workshop on Clinical Pharmacology of HIV Therapy
April 22-24, 2013
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Split Dosing Versus Single Dose of Long-Acting Injected Integrase Inhibitor
  14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Split administration of GSK1265744, an injected nanosuspension integrase inhibitor, yielded higher GSK744 12-week area under the concentration-time curve (AUC) and maximum concentration (Cmax) than single administration of the same total dose, according to results of a study in 16 healthy HIV-negative volunteers [1]. But another AUC result suggested dosing did not affect extent of absorption.
Being developed for HIV treatment and prevention (as preexposure prophylaxis), GSK744 yielded half-lives ranging from 21 to 50 days after a single injection of various test doses in 56 healthy volunteers [2]. Two doses of the nanoparticle-shrouded integrase inhibitor protected eight macaques from repeated rectal challenge with simian HIV [3].
The new study involved 8 men and 8 women randomized to receive a single 400-mg gluteal injection of GSK744 (4 men and 4 women) or two 200-mg injections (4 men and 4 women). The researchers collected serial plasma samples for 12 weeks and then monthly until the concentration fell below 0.01 ug/mL. Men gave rectal biopsy samples and women gave cervicovaginal tissue samples at weeks 2 and 8 (in the single-dose group) and weeks 4 and 12 (in the split-dose group).
Volunteers tolerated GSK744 well, regardless of dosing strategy, with no serious adverse events. All study participants provided plasma and tissue samples through at least week 12. Average (and standard deviation) plasma AUCs were higher in the 0-W4 and 0-W12 measures with split dosing than with a single dose, but AUC(0-infinity) was similar with split and single dosing:
Single 400-mg dose:
AUC(0-W4): 319 (159) ug x h/mL
AUC(0-W12): 1077 (565) ug x h/mL
AUC(0-infinity): 2763 (900) ug x h/mL
Split 200/200-mg dose:
AUC(0-W4): 737 (392) ug x h/mL
AUC(0-W12): 1965 (808) ug x h/mL
AUC(0-infinity): 2934 (1101) ug x h/mL
Average (standard deviation) Cmax values were 0.79 ug/mL (0.45) with single-dose administration and 1.57 ug/mL (0.74) with split dosing. Median time to maximum concentration of GSK744 came at week 10 with the single 400-mg dose and at week 2 after split dosing.
Median tissue/plasma ratios were 0.16 with split dosing and 0.20 with single dosing in cervical tissue, 0.19 with split dosing and 0.28 with single dosing in vaginal tissue, and undetectable and 0.08 in rectal tissue. Higher tissue concentrations correlated with higher plasma concentrations.
The researchers noted that GSK744 plasma concentrations were lower than target therapeutic concentrations, as they had predicted because of the subtherapeutic dose used. AUC(0-W4), AUC(0-W12), and Cmax levels were about 2 times higher with split dosing than with a single dose. Similar AUC(0-infinity) values with split and single dosing, the investigators proposed, suggest that split dosing does not affect the extent of absorption. They believe their findings "suggest therapeutic range GSK1265744 plasma concentrations will produce tissue drug concentrations that exceed protein-adjusted IC90 upon repeat long-acting parenteral administration."
1. Ford SL, Margolis D, Chen S, Gould E, Spreen W. Plasma and tissue GSK1265744 pharmacokinetics following long-acting parenteral administration in healthy male and female subjects. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_02.
2. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference. July 22-27, 2012. Washington, DC. Poster TUPE040.
3. Andrews C, Gettie A, Russell­Lodrigue K, et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 24LB. http://www.natap.org/2013/CROI/croi_10.htm