Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques

Abstract

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.

Keywords: HIV pre-exposure prophylaxis; biodegradable implant; etonogestrel; islatravir; multipurpose prevention technologies.

Figure 1

In vitro drug release from PCL implants. (A) Daily in vitro release profiles of ISL from implants run in parallel with the in vivo study in macaques with average release rates of 41.9 ± 5.5 µg/day (ISL-62 mg) and 65.6 ± 8.2 µg/day (ISL-98 mg). (B) Daily in vitro release profile of ENG from implants run in parallel with the in vivo study with an average release rate of 31.1 ± 9.6 µg/day.

Figure 2

Study Design. (A) The first group of 3 macaques received ISL-62 mg implant (right arm) to assess the low ISL dose and a month later received an ISL-98 mg implant in their left arm to evaluate the high ISL dose. (B) The second group of 3 macaques received ISL-98 mg implant (right arm) to assess the mid ISL dose and received an ENG-33 mg implant in their left arm a month later. The ISL-98 mg implant was removed at 3 months. The ENG implant was removed after 6 months.

Figure 3

Pharmacokinetics of ISL and ISL-TP. (A) Median [range] plasma ISL and (B) PBMC ISL-TP levels for the low-dose ISL-62 mg (blue), mid-dose ISL-98 mg (red), and high-dose ISL-62 and ISL-98 mg (green). Day zero for ISL-62 mg and ISL-98 mg animals was the day of the first implantation. Day zero for the ISL-62 & ISL-98 mg was the day of the second implantation. The pharmacokinetic benchmark of 50 fmol ISL-TP/10⁶ PBMCs (Target) and lower limit of quantification (LLOQ) are shown with dashed lines. (C) Dose linearity between the in vitro release rate and plasma ISL (left axis, circles) and PBMC ISL-TP (right axis, squares). (D) Pharmacokinetic tail of ISL plasma ISL (top) and PBMC ISL-TP (bottom) after removal of ISL-98 mg from the mid-dose group.

Figure 4

Plasma progesterone (left axis, red) and ENG (right axis, purple) in macaques that received ISL-98 mg and ENG-33 mg implants.

Figure 5

The effect of ISL and ENG co-implantation on ISL pharmacokinetics was determined by evaluating ISL analytes. (A) Plasma ISL, (B) PBMC ISL-TP, and (C) mucosal tissue ISL-TP when animals had a single ISL-98 mg implant (open shapes) compared to after co-implantation with ENG (red shapes). (D) Ratios of ISL-TP to the natural nucleotide competitor, dATP, were determined for each tissue. Each individual animal (n = 3) is shown with a different shape.

Figure 6

Implant site reactions were scored weekly for erythema and edema using a modified Draize scale. (A) Heat map of weekly Draize scoring of implant site for each animal (columns PT1-PT6) and each implant (ISL-62, ISL-98 or ENG-33 mg). Colors indicate severity of implant site reaction (0 = none/green, 1 = mid, 2 = well-defined, 3 = moderate, 4 = severe/red). Red boxes indicate when ISL-98 mg implants were deemed broken. (B) Median Draize scores for ENG-33 (purple), ISL-62 (blue), intact ISL-98 mg implants (red, unfilled box), and broken ISL-98 mg implants (red, filled box).