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Pharmacokinetics of Long-acting Tenofovir Alafenamide (GS-7340)
Subdermal Implant for HIV Prophylaxis
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Antimicrob. Agents Chemother.
AAC Accepted Manuscript Posted Online 20 April 2015
Manjula Gunawardana,1 Mariana Remedios-Chan,2 Christine S. Miller,1 Rob Fanter,1 Flora Yang,1 Mark A. Marzinke,3,4 Craig W. Hendrix,3 Martin Beliveau,5 John A. Moss,1 Thomas J. Smith,1,2 and Marc M. Baum#1
1Department of Chemistry, Oak Crest Institute of Science, 128-132 W. Chestnut Ave., Monrovia,California
2Auritec Pharmaceuticals, Inc., 2285 E. Foothill Blvd., Pasadena, California 3Department of Medicine, Johns Hopkins University, 600 North Wolfe Street, Osler 500, Baltimore, Maryland
4Department of Pathology, Johns Hopkins University, 1800 Orleans Street, Sheikh Zayed Tower, B1020-G, Baltimore, Maryland
5Pharsight Consulting Services, 2000 Peel St., Montreal, Quebec, Canada
Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1 negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to dosing period, sustained release or “long-acting” ARV formulations hold significant promise for increasing the effectiveness of HIV-1 pre-exposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg d-1 in vitro was evaluated in beagle dogs over 40 d for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median 0.85 ng ml-1, IQR 0.60-1.50 ng ml-1) and tenofovir (TFV, median 15.0 ng ml-1, IQR 8.8-23.3 ng ml-1), the product of in vivo TAF hydrolysis. High concentrations (median 512 fmol/106 cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells, levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates successful proof-of-principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.
Conclusion. A long-acting TAF implant has translational potential as a candidate for HIV-1 prophylaxis in vulnerable populations. Sustained release TAF delivery could improve drug adherence and reduce transmission compared to daily oral dosing. A TAF implant also holds potential as part of a highly active antiretroviral therapy (HAART) regimen for the treatment of HIV-1/AIDS especially when combined with other parenteral sustained release ARV formulations.
The prodrug TAF (EC50 5 nM) is 1,000 times more potent than TFV and 10 times more potent than the prodrug TDF (24), making TAF the logical choice as the TFV moiety in the development of a long-acting formulation. Oral TAF also leads to lower plasma TFV exposure than oral TDF (25), a favorable characteristic for long-term safety.
Here, a novel sub dermal implant for sustained release TAF is described. The geometry and size of the device is based on widely used contraceptive implants. The prototype device was evaluated for PKs and preliminary safety in beagle dogs over 40 days. Sustained TFV-DP levels in PBMCs significantly exceeded those believed to be required for efficacious HIV-1 PrEP.
Novel implant design for the sustained delivery of water-soluble drugs. A sustained release formulation of TAF has not been reported. The implant design described here is novel and builds on the success of our pod-intravaginal ring (pod-IVR) system for sustained, highly controlled vaginal drug delivery (29). The implant consists of a drug-filled, PVA-coated silicone cylinder with orthogonal delivery channels (Fig. 1).....
Physical characteristics of the TAF LA implant. The physical characteristics of the sustained release TAF implant are presented in Table 1 and Figure 1. The orange-brown color of the implant (Table 1) is the result of dehydration of the PVA backbone during thermal processing, leading to the formation of conjugated double bonds (36, 37). In vitro cumulative release profiles (Fig. 2, Table 1) exhibited burst-free, sustained release with zero-order (linear) kinetics over 30 d.
Residual drug analysis on the used implants showed that, on average, 98% of the TAF payload was delivered over the 40-d study: residual TAF, 0.85 ± 0.81 mg (mean ± SD). Only traces of TFV (mean 0.13 mg) were detectable. The TAF implant in vitro dissolution rate (Kd 0.92 mg d-1, Table 1) was not statistically significantly different (P 0.1859, two-tailed unpaired t test with Welch's correction) from the in vivo release rate (Ka 1.07 mg d-1, Table 1).
The TAF implants maintained sustained plasma levels of TAF and TFV as well as PBMC TFV-DP concentrations for 40 d (Fig. 3).
In this preliminary study, a subcutaneous implant delivering TAF at a rate of 1.07 ± 0.02 mg d-1 for 40 d in beagle dogs maintained median PBMC TFV-DP levels of 512 fmol/106 cells over the first 35 d. This achieved median concentration is 11-32 times higher than the protective target from iPrEX (corresponding to a TFV-DP concentration range of 48-16 fmol/106 cells) Simple allometric scaling (44, 45) (exponent 0.75) from beagle dogs (mean weight 10.8 kg) to humans (70 kg) affords a preliminary, lower target daily TAF release rate of 0.14 mg d-1 to maintain a median TFV-DP PBMC concentration of 16 fmol/106 cells. The concentration of PBMCs in beagle dog whole blood (mean 1.6×106 cells/mL, SD 0.7×106 cells/mL) was comparable to typical values for HIV-negative humans. A one-year implant therefore would need to contain at least 51 mg TAF (0.14 mg d-1 × 365 d), a feasible quantity for an implant with practical physical dimensions.

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