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Long-acting injectable antiretrovirals for HIV treatment and prevention.

Spreen WR, Margolis DA, Pottage JC - Curr Opin HIV AIDS (2013)

Bottom Line: Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations.The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations.Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment.

View Article: PubMed Central - PubMed

Affiliation: aGlaxoSmithKline, Research Triangle Park, North Carolina bViiV Healthcare, Philadelphia, Pennsylvania, USA.

ABSTRACT

Purpose of review: Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents.

Recent findings: The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials.

Summary: Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents - different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses - offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.

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Related in: MedlinePlus

Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation [19]. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-type HIV-1 of 0.166 μg/ml.
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Figure 1: Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation [19]. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-type HIV-1 of 0.166 μg/ml.

Mentions: Two phase I studies have reported the tolerability, safety and pharmacokinetics of GSK1265744 long-acting injection [19,21]. In a randomized, placebo-controlled, double-blinded, single-dose study, 56 HIV-uninfected adults received GSK1265744 as a gluteal intramuscular injection of 100, 200, 400 or 800 mg or an subcutaneous abdominal injection of 100, 200 or 400 mg or placebo injection vehicle. Following single intramuscular or subcutaneous injection, plasma drug concentrations increased rapidly over the first week, with sustained mean plasma concentrations above the PA–IC90 for approximately 24 weeks or longer for doses of at least 200 mg, as shown in Fig. 1.


Long-acting injectable antiretrovirals for HIV treatment and prevention.

Spreen WR, Margolis DA, Pottage JC - Curr Opin HIV AIDS (2013)

Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation [19]. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-type HIV-1 of 0.166 μg/ml.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815009&req=5

Figure 1: Mean plasma levels of GSK1265744 over time following single-dose administration of long-acting formulation [19]. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-type HIV-1 of 0.166 μg/ml.
Mentions: Two phase I studies have reported the tolerability, safety and pharmacokinetics of GSK1265744 long-acting injection [19,21]. In a randomized, placebo-controlled, double-blinded, single-dose study, 56 HIV-uninfected adults received GSK1265744 as a gluteal intramuscular injection of 100, 200, 400 or 800 mg or an subcutaneous abdominal injection of 100, 200 or 400 mg or placebo injection vehicle. Following single intramuscular or subcutaneous injection, plasma drug concentrations increased rapidly over the first week, with sustained mean plasma concentrations above the PA–IC90 for approximately 24 weeks or longer for doses of at least 200 mg, as shown in Fig. 1.

Bottom Line: Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations.The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations.Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment.

View Article: PubMed Central - PubMed

Affiliation: aGlaxoSmithKline, Research Triangle Park, North Carolina bViiV Healthcare, Philadelphia, Pennsylvania, USA.

ABSTRACT

Purpose of review: Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents.

Recent findings: The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials.

Summary: Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents - different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses - offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.

Show MeSH
Related in: MedlinePlus