Pharmacokinetics, Safety, and Tolerability With Repeat Doses of GSK1265744 and Rilpivirine (TMC278) Long-Acting Nanosuspensions in Healthy Adults

Spreen, William; Williams, Peter; Margolis, David; Ford, Susan L.; Crauwels, Herta; Lou, Yu; Gould, Elizabeth; Stevens, Marita; Piscitelli, Stephen C.

doi:10.1097/qai.0000000000000365

Cited by 102 publications

(112 citation statements)

References 4 publications

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“…A Phase I, open-label, ninecohort, parallel study of healthy adults who received intramuscular and subcutaneous injections demonstrated that the long-acting injection of 744 may be useful as a monthly or less frequently administered therapy for HIV infection [81]. The injections were well tolerated, with grade 1 injection site reactions being the most commonly reported adverse effect [82]. A Phase IIa, double-blind, placebo-controlled study showed that once-daily oral administration of 744 may be useful based on low-milligram dose (5 or 30 mg), low variability in pharmacokinetics, favorable safety profile and effective antiretroviral activity [83].…”

Section: Current Role Of Instis In the Treatment Of Hiv Infectionmentioning

confidence: 97%

Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection

Mohamed

Kalabalik

Sharma

2015

Expert Review of Anti-infective Therapy

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Integrase strand transfer inhibitors (INSTIs) are oral antiretroviral agents used against HIV infection. There are three agents available, including raltegravir, elvitegravir and dolutegravir, some of which are available as combination medications with other antiretroviral drugs. The efficacy and safety of INSTIs in treatment-naïve and experienced HIV-infected patients have been established by multiple studies. Based on the current practice guidelines, INSTI-based regimens are considered as one of the first-line therapies for treatment-naïve HIV-infected patients. There are new INSTIs in development to improve the resistance profile and to decrease the frequency of drug administration.

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Section: Current Role Of Instis In the Treatment Of Hiv Infectionmentioning

confidence: 97%

Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection

Mohamed

Kalabalik

Sharma

2015

Expert Review of Anti-infective Therapy

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“…During these trials, patients failing RPV-based ART also tended to select unique NNRTI-associated resistance mutations in reverse transcriptase (RT) compared with those on an efavirenz-based regimen (20). Long-acting rilpivirine (RPV LA) is an injectable nanoparticle formulation and has been shown to be safe and tolerable, with detectable drug concentrations maintained in plasma and tissues weeks after a single injection (21)(22)(23)(24). Multiple clinical trials are under way to test safety and acceptability of RPV LA as PrEP in HIV-1-uninfected men and women (13).…”

mentioning

confidence: 99%

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

Melody

McBeth

Kline

et al. 2015

Antimicrob Agents Chemother

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c Preexposure prophylaxis (PrEP) using antiretroviral drugs is effective in reducing the risk of human immunodeficiency virus type 1 (HIV-1) infection, but adherence to the PrEP regimen is needed. To improve adherence, a long-acting injectable formulation of the nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV LA) has been developed. However, there are concerns that PrEP may select for drug-resistant mutations during preexisting or breakthrough infections, which could promote the spread of drug resistance and limit options for antiretroviral therapy. To address this concern, we administered RPV LA to macaques infected with simian immunodeficiency virus containing HIV-1 RT (RT-SHIV). Peak plasma RPV levels were equivalent to those reported in human trials and waned over time after dosing. RPV LA resulted in a 2-log decrease in plasma viremia, and the therapeutic effect was maintained for 15 weeks, until plasma drug concentrations dropped below 25 ng/ml. RT mutations E138G and E138Q were detected in single clones from plasma virus in separate animals only at one time point, and no resistance mutations were detected in viral RNA isolated from tissues. Wild-type and E138Q RT-SHIV displayed similar RPV susceptibilities in vitro, whereas E138G conferred 2-fold resistance to RPV. Overall, selection of RPV-resistant variants was rare in an RT-SHIV macaque model despite prolonged exposure to slowly decreasing RPV concentrations following injection of RPV LA.

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“…Cabotegravir is formulated as a long‐acting injectable and amenable to monthly or less frequent dosing 3, 4. As both an HIV‐1 treatment and prevention modality, CAB is expected to be coadministered with hormonal contraceptives in HIV‐infected and uninfected women.…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

Trezza¹,

Ford

Gould

et al. 2017

Brit J Clinical Pharma

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AimsThis study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus‐1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)–containing oral contraceptive (OC) in healthy women.MethodsIn this open‐label, fixed‐sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1–10 alone and with oral CAB 30 mg once daily Days 11–21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle‐stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations.ResultsTwenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07–1.18) and 1.05 (0.96–1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97–1.08) and 0.92 (0.83–1.03), respectively. Steady‐state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle‐stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed.ConclusionsRepeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

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Pharmacokinetics, Safety, and Tolerability With Repeat Doses of GSK1265744 and Rilpivirine (TMC278) Long-Acting Nanosuspensions in Healthy Adults

Abstract: These data support the potential application of dual-therapy 744 LA and RPV LA for treatment of HIV-1 infection.

Cited by 102 publications

References 4 publications

Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection

Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

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