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Clinical Science

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV

Matthews, Randolph P. MD, PhDa; Jackson Rudd, Deanne PhDa; Zhang, Saijuan PhDa; Fillgrove, Kerry L. PhDa; Sterling, Laura M. MD, MPHb; Grobler, Jay A. PhDa; Vargo, Ryan C. PhDa; Stoch, S. Aubrey MDa; Iwamoto, Marian MD, PhDa

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1, 2021 - Volume 88 - Issue 3 - p 314-321
doi: 10.1097/QAI.0000000000002755
  • Open

Abstract

INTRODUCTION

Although available combination antiretroviral therapy is highly effective for the treatment of HIV-1 infection, new agents with improved safety and tolerability, more potent antiviral activity, especially against drug-resistant HIV-1 variants, and additional attributes such as extended interval dosing have the potential to transform care.1,2 Furthermore, while HIV-1 pre-exposure prophylaxis clearly decreases transmission among at-risk individuals,3 uptake and efficacy can be variable4 and novel strategies that improve prevention may be transformative.

Islatravir (MK-8591) is in clinical development as a novel nucleoside analog for the treatment and prevention of HIV-1 infection.5,6 Islatravir is converted by intracellular kinases to its active form, islatravir-triphosphate (ISL-TP), which inhibits reverse transcriptase (RT) by multiple mechanisms of action, including inhibition of translocation, and has potent activity against wild-type and common drug-resistant HIV-1 variants.7–9

Previous clinical trials in adults without HIV demonstrated that the plasma half-life of islatravir after single-dose administration is ∼49–61 hours, whereas ISL-TP has a longer intracellular half-life of ∼118–171 hours.10 Similar pharmacokinetics (PK) have been demonstrated in people living with HIV-1 (PLWH).10 Adenosine deaminase is the only known contributor to islatravir metabolism,11 and islatravir is not expected to have significant drug–drug interactions.12–14 In addition, food had little impact on islatravir PK.10 The long intracellular half-life and high potency of ISL-TP allow for a variety of islatravir dosing options, ranging from once daily (QD) to less frequent dosing schedules.

A study was conducted to evaluate the PK of both islatravir in plasma and ISL-TP in peripheral blood mononuclear cells (PBMCs) after QD dosing in adults without HIV infection. Virologic response is often predicted using the inhibitory quotient (IQ), which is defined as the ratio of drug concentration at trough (Ctrough) over the intracellular concentration required for efficacy [usually, the in vitro concentration of drug resulting in 50% inhibition of wild-type virus (IC50)].14 Preliminary clinical efficacy was demonstrated in a previously conducted islatravir single-dose 7-day monotherapy trial in treatment-naive PLWH. Doses as low as 0.5 mg demonstrated effective viral load lowering.10 From these data, an ISL-TP Ctrough target of 0.05 pmol/106 cells was established based on the lowest concentration measured at day 7 postdose. In vitro studies showed that the IC50 against wild-type HIV-1 is approximately 0.00974 pmol/106 cells, whereas the important nucleoside reverse transcriptase inhibitor (NRTI)-resistance variants, M184I and M184V, confer 3.9-fold and 5.0-fold reductions in islatravir potency, respectively.15,16 Thus, the calculated IQ is 5 for wild-type HIV-1 and ≥1 for M184I/V when the trough concentration is maintained at or above ∼0.05 pmol/106 cells, which is a PK threshold of interest for islatravir.

In addition to plasma and PBMC PK assessment, concentrations of ISL-TP were measured in rectal and vaginal biopsies to assess tissue penetration at potential initial sites of HIV-1 replication and transmission. Safety and tolerability of QD administration were also evaluated.

METHODS

Study Design and Participants

This trial (MK-8591 Protocol 009) was a 3-panel, randomized, double-blind, placebo-controlled, multiple-dose study conducted between March and September 2017. In each panel, participants were randomly assigned to receive islatravir or placebo in a 3:1 ratio. In panel A, islatravir 5 mg or placebo was administered orally QD on days 1 through 42. In panel B, islatravir 0.25 mg or placebo was administered QD on days 1 through 28, and in panel C, islatravir 0.75 mg or placebo was administered QD on days 1 through 28.

Male and female adults without HIV between 19 and 55 years and with a body mass index between 19.0 and 32.0 kg/m2 at screening were eligible to enroll in this study. Women enrolled were of nonchildbearing potential. Participants with a presence or history of a clinically significant medical or psychiatric condition were excluded. Although the potential for interaction with islatravir was considered low, participants were prohibited from taking any drugs that could significantly interact with CYP enzymes or P-glycoprotein. The trial was conducted following Good Clinical Practice Guidelines and was approved by Chesapeake Research Review, Inc., Columbia, MD. All participants provided written informed consent before any study procedures were performed.

The primary endpoint was to assess the safety and tolerability of multiple oral QD doses of islatravir in healthy adult subjects. Additional endpoints included characterizing islatravir plasma PK, intracellular PK of ISL-TP, the urinary excretion of islatravir, and, in a subset of participants, the concentrations of islatravir and ISL-TP in rectal or vaginal tissue.

Clinical Assessments

Blood samples for islatravir and ISL-TP PK analyses were collected at selected time points throughout the study up to 1008 (±72) hours (42 ± 3 days) postdose in panel A and up to 840 (±72) hours (28 ± 3 days) postdose in panels B and C. In addition, biopsies from rectal (men only) or vaginal tissue were collected and analyzed for ISL-TP concentrations on days 43 (panel A) and 29 (panels B and C). Urine samples were collected for PK assessment of islatravir at predose on day 1 in all panels and over prespecified 24-hour intervals.

Safety and tolerability were evaluated based on adverse event (AE) monitoring, physical examinations, vital signs, electrocardiography, and laboratory safety tests. All clinical AEs reported by the participant or observed by the investigator were graded as mild, moderate, or severe in intensity. AEs were categorized according to MedDRA version 20.0.

Analytical Methods

Islatravir concentrations in plasma were determined by Syneos Health, Inc. (Quebec City, Quebec, Canada) using a validated high-performance liquid chromatographic tandem mass spectrometric (HPLC MS/MS) method.17 The analytical range was 0.10–100 ng/mL (0.341–341 nM). The lower limit of quantitation was defined by the low end of the analytical range.

Collection of PBMCs for the ISL-TP assay included isolation of the PBMCs from blood samples by density gradient centrifugation, after which the plasma layer from each sample was removed and discarded. The isolated cells were stabilized in 70% methanol before the assay procedure. ISL-TP concentration in PBMCs was determined by Merck & Co., Inc. (West Point, PA) using a reversed-phase liquid chromatography (LC) and tandem mass spectrometric detection employing a turbo ion spray (TIS).17 The analytical range was 0.10–40.0 ng/mL (0.188–75.0 nM).

Concentrations of islatravir in plasma and ISL-TP in PBMCs were converted into molar units (nM) using the molecular weight of 293.3 and 533.1 g/mol, respectively. Before performing the PK analysis, the PBMC ISL-TP concentration in molar units was converted to pmol/106 cells using the following calculation: pmol/106 = [(concentration in nM) × (cell dilution of X mL)]/(cell count in 106 cells), where X = 0.7 if total cell count ≤ 35 × 106 cells and X = 1.4 if 35 × 106 cells <total cell count ≤70 × 106 cells.

The following PK parameters were determined for plasma islatravir and PBMC ISL-TP: area under the concentration–time curve from 0 to 24 hours after dosing (AUC0–24), maximum concentration of drug in plasma (Cmax), average steady-state concentration of drug in plasma during the dosing interval (Cavg), plasma drug concentration at 24 hours after dosing (C24), time to reach Cmax (Tmax), and apparent terminal half-life (t1/2).

Urine islatravir concentrations were determined by Merck & Co., Inc. using a reversed-phase LC and tandem mass spectrometric detection employing a TIS. The analytical range was 0.1 to 100 ng/mL (34.1 nM–34,100 nM). The lower limit of quantitation is defined by the low end of the analytical range.

The following urine PK parameters were calculated for islatravir: total amount of unchanged drug excreted in urine from 0 to 24 hours (Ae0–24), renal clearance (CLr), and the percent of islatravir dose excreted in urine from 0 to 24 hours (fe).

Islatravir and ISL-TP concentrations in rectal and vaginal biopsy tissue were determined by Merck & Co., Inc. (West Point, PA) using a reversed-phase LC and tandem mass spectrometric detection employing a TIS. The analytical range was 0.20–50.0 ng/mL for both analytes, corresponding to 0.682–170 nM and 0.375–93.8 nM for islatravir and ISL-TP, respectively. Tissue islatravir and ISL-TP were homogenized after a 1:19 dilution in 70:30 methanol:water (v:v) to enable extraction and stabilization of the analytes of interest. Islatravir and ISL-TP concentrations in the resulting homogenates were determined using LCMS and reported in units of ng/mL (because of the sample being a homogenate). These results were corrected for the 20X dilution factor and converted from ng to fmol units using the molecular weight of either islatravir or ISL-TP (see above). A final correction step from units of volume to units of mass (ie, grams of tissue) was applied, assuming that 1 mL = 1 g tissue.

To compare tissue levels of antiretrovirals against threshold activity levels, several assumptions were made to account for the complexity of the biopsy samples. Rectal and vaginal biopsy specimens are cellularly heterogeneous, containing large epithelial cells as well as much smaller inflammatory cells and fibroblasts. In addition, the relative degree of uptake of antiretrovirals into cell types other than PBMCs is generally not known. Tissue amounts of antiretrovirals are typically reported as fmol/g while PBMC levels are typically reported as pmol (or fmol) per million cells or directly as molar concentrations. To facilitate the comparisons shown below, cell volumes of 0.2 pL for PBMCs18 and 1.2 pL for epithelial cells were assigned, and the heterogeneous makeup of biopsy samples was simplified to include a range of possibilities.19–22

Statistical Methods

PK parameter values were determined from concentration–time data for plasma islatravir, concentration–sample weight for urine islatravir, and concentration (including cell count)-time data for ISL-TP by using a noncompartmental approach using Phoenix WinNonlin version 6.3 (Certara, Parsippany, NJ). PBMC ISL-TP AUC0–24, Cmax, and C24 and plasma islatravir AUC0–24, Cmax, and C24 were natural log (ln)-transformed and analyzed using a linear mixed-effects model containing fixed effects for treatment, day, and treatment-by-day interaction and a random effect for participants. The 90% confidence intervals for the geometric means (GMs) were constructed for each treatment on each PK sampling day. Cavg was calculated as the quotient of AUC0–24 and the dosing interval 24 hours (AUC0–24/24). The apparent terminal t1/2 was calculated as the quotient of the ln of 2 and λz [ln(2)/λz], where λz is the apparent first-order terminal elimination rate constant calculated from the slope of the linear regression of the terminal ln-linear portion of the plasma concentration–time profile. At least 3 consecutive time points in the terminal ln-linear phase, excluding Cmax, were used for the apparent terminal t1/2 determination. For urinary PK parameters, Ae0–24, CLr, and fe, Ae0–24 was calculated as the concentration multiplied by the weight of urine collected and assuming 1 g of urine = 1 mL of urine. CLr was calculated as the quotient of Ae0–24 and plasma islatravir AUC0–24 (Ae0–24/AUC0–24), and fe was calculated as Ae0–24 divided by the dose and expressed as a percentage [(Ae0–24/dose) × 100].

Descriptive statistics (non–model-based) for plasma islatravir, urine islatravir, and PBMC ISL-TP were also provided by day and treatment: sample size, arithmetic mean (AM), SD, arithmetic percent coefficient of variation (CV), median, minimum, maximum, GM, and geometric CV (GCV).

RESULTS

Study Population

Thirty-six participants were enrolled (12 per panel; 9 active and 3 placebo), and 35 participants completed the study. One participant in panel B completed study treatment and all PK assessments and therefore was included in the analysis but withdrew from the study before completing the day 63 follow-up visit. In total, 30 participants were male and 6 were female, the mean age was 38.3 years (range: 19–55 years), and the mean body mass index was 27.8 kg/m2 (range: 20.2–31.9 kg/m2). Overall, 29 participants were White, 5 were Black or African American, 1 was American Indian or Alaska Native, and 1 was of mixed heritage.

PK of Islatravir in Plasma

The PK of islatravir in plasma and urine are summarized in Table 1. Islatravir was rapidly absorbed, with a median Tmax of 0.55–1.00 hour. PK parameter values seemed approximately dose proportional. The plasma islatravir AUC0–24 accumulation ratio was 1.5-fold to 1.8-fold across all dose levels on day 28, and concentrations seemed to be approaching a steady state between day 14 and day 21. C24 after the first dose was below the limit of quantitation for all participants who received the 0.25-mg dose and for 4 participants who received the 0.75-mg dose (Fig. 1A). The apparent terminal t1/2 of islatravir in plasma increased with dose (86.9–230 hours) (Fig. 1B).

TABLE 1. - PK of Islatravir in Plasma and Urine After Administration of Single and Multiple Once-Daily Doses in Adults Without HIV
PK Parameters Day Islatravir Dose
0.25 mg 0.75 mg 5 mg
n GM GCV n GM GCV n GM GCV
AUC0–24 (nM h) 1 9 17.5 14.4 9 53.4 21.4 9 395 20.7
28 9 32.0 12.5 9 87.2 19.9 9 622 13.8
42 NA NA NA NA NA NA 9 675 14.8
Cmax (nM) 1 9 7.81 27.7 9 18.4 34.1 9 124 32.5
28 9 8.51 20.5 9 18.4 33.2 9 138 28.0
42 NA NA NA NA NA NA 9 141 26.2
Cavg (nM) 1 9 0.728 14.4 9 2.22 21.4 9 16.5 20.7
28 9 1.33 12.5 9 3.63 19.9 9 25.9 13.8
42 NA NA NA NA NA NA 9 28.1 14.8
Tmax (h) 1 9 0.55 (0.51, 1.00) 9 0.58 (0.50, 1.01) 9 1.00 (0.50, 1.00)
28 9 0.59 (0.52, 1.00) 9 1.00 (0.50, 2.00) 9 0.59 (0.52, 1.01)
42 NA NA NA NA NA NA 9 1.00 (0.50, 1.01)
Apparent terminal t1/2 (h) 28 9 86.9 89.5 9 122 23.1 NA NA NA
42 NA NA NA NA NA NA 9 230 10.2
Ae* (nmol) 1 NA NA NA 8 396 295.4 9 4490 35.8
28 NA NA NA 9 697 103.5 NA NA NA
42 NA NA NA NA NA NA 9 6780 17.6
CLr* (L/h) 1 NA NA NA 8 7.76 257.1 9 11.4 44.2
28 NA NA NA 9 7.99 90.4 NA NA NA
42 NA NA NA NA NA NA 9 10.0 21.4
Fe* (%) 1 NA NA NA 8 15.5 295.4 9 26.3 35.8
28 NA NA NA 9 27.2 103.5 NA NA NA
42 NA NA NA NA NA NA 9 39.8 17.6
GMs and GCVs presented in this table are non–model-based. Median (min and max) reported for Tmax. 0.25 mg islatravir (panel B): 0.25 mg of islatravir (1 × 0.25 mg capsule) administered QD for 28 consecutive days. 0.75 mg islatravir (panel C): 0.75 mg of islatravir (3 × 0.25 mg capsule) administered QD for 28 consecutive days. 5 mg islatravir (panel A): 5 mg of islatravir (5 × 1 mg capsule) administered QD for 42 consecutive days.
*Urine PK parameters: Urine samples were not analyzed for 0.25 mg islatravir and sampling ended on day 28 for 0.25 and 0.75 mg islatravir.
NA, not applicable.

FIGURE 1.
FIGURE 1.:
Plasma C24 concentration–time profiles (semi-log scale) of islatravir in adults without HIV (n = 9 per dose). A, Multiple QD doses of islatravir (through day 28 or 42). B, Final dose (day 28 or day 42) after QD administration.

PK of ISL-TP in PBMCs

The PK of ISL-TP in PBMCs are summarized in Table 2. AUC and Cmax were approximately dose proportional. After multiple-dose administration, the ISL-TP AUC0–24 accumulation ratio in PBMCs was approximately 10-fold by day 28. PBMC levels of ISL-TP reached a steady state by day 28 (Fig. 2A) and were maintained above the PK threshold for ∼30 days after cessation of dosing (Fig. 2B). The apparent terminal t1/2 of ISL-TP was 177–209 hours.

TABLE 2. - PK of ISL-TP in PBMCs After Administration of Single and Multiple Once-Daily Doses of Islatravir in Adults Without HIV
PK Parameters Day Islatravir Dose
0.25 mg 0.75 mg 5 mg
n GM GCV n GM GCV n GM GCV
AUC0–24 (pmol h/106 cells) 1 9 2.36 20.1 9 7.72 31.9 9 57.3 21.5
28 9 27.3 40.4 9 72.0 24.4 9 520 12.5
42 NA NA NA NA NA NA 9 626 27.3
Cmax (pmol/106 cells) 1 9 0.124 26.3 9 0.478 41.3 9 3.11 31.2
28 9 1.80 44.1 9 6.87 58.5 9 30.5 15.8
42 NA NA NA NA NA NA 9 40.7 24.7
Cavg (pmol/106 cells) 1 9 0.099 20.0 9 0.323 31.9 9 2.39 21.5
28 9 1.14 40.4 9 3.00 24.4 9 21.7 12.5
42 NA NA NA NA NA NA 9 26.1 27.3
Tmax (h) 1 9 23.9 (4.00, 24.0) 9 23.9 (8.00, 23.9) 9 12.0 (4.00, 23.9)
28 9 8.00 (0.00, 12.0) 9 4.01 (4.00, 168) 9 4.01 (0.00, 12.0)
42 NA NA NA NA NA NA 9 12.0 (1.02, 72.0)
Apparent terminal t1/2* (h) 28 8 186 16.4 8 177 18.3 NA NA NA
42 NA NA NA NA NA NA 9 209 11.4
GMs and GCVs presented in this table are non–model-based.
Median (min, max) reported for Tmax.
0.25 mg islatravir (Panel B): 0.25 mg islatravir (1 x 0.25 mg capsule) administered QD for 28 consecutive days.
0.75 mg islatravir (Panel C): 0.75 mg islatravir (3 x 0.25 mg capsule) administered QD for 28 consecutive days.
5 mg islatravir (Panel A): 5 mg islatravir (5 × 1 mg capsule) administered QD for 42 consecutive days.
*The sampling interval for 0.25 mg and 0.75 mg dose was 24 hours postdose on Day 1 and 840 hours postdose on Day 28. For the 5 mg dose, the sampling interval was 24 hours postdose on Days 1 and 28, and 1008 hours postdose on Day 42.
AUC0−24, area under the concentration-time curve from 0 to 24 hours after dosing; Cavg, average steady-state concentration of drug in plasma during the dosing interval; Cmax, maximum concentration of drug in plasma; GCV, geometric coefficient of variation; GM, geometric mean; NA, not applicable; PK, pharmacokinetic; QD, once daily; t½, half-life; Tmax, time to reach Cmax.

FIGURE 2.
FIGURE 2.:
PBMC concentration–time profiles (semi-ln scale) of ISL-TP in adults without HIV (n = 9 per dose). A, Multiple QD doses of islatravir (through day 28 or 42)*. B, Final dose (day 28 or day 42) of islatravir after QD administration. C, Single oral dose of islatravir. *Trough concentrations. Error bars indicate SD. Horizontal gray line denotes a PK threshold of 0.05 pmol/106.

The prespecified intracellular ISL-TP PK threshold of 0.05 pmol/106 cells was exceeded at 24 hours after the first dose at all dose levels. The GM C24 of ISL-TP exceeded the PK threshold by 2.3-fold, 7.9-fold, and 54-fold at the 0.25-mg, 0.75-mg, and 5 mg-dose levels, respectively (Fig. 2C).

PK of Islatravir in Rectal and Vaginal Tissue

In addition to PK assessment of plasma and PBMCs, rectal and vaginal biopsies were obtained on a subset of participants; this was an optional component of the trial, and not all subjects participated. The samples were assayed for ISL-TP to gauge levels of active TP in tissues important for HIV transmission. In rectal tissue biopsies, the AM ISL-TP concentrations were as follows:

  • 11,400 ± 3000 fmol/g tissue after 0.25 mg (n = 8),
  • 53,700 ± 21,900 fmol/g tissue after 0.75 mg (n = 4), and
  • 206,000 ± 22,000 fmol/g tissue after 5 mg (n = 3).

Fewer female participants agreed to have biopsies. No vaginal biopsies were obtained after 0.25 mg. In vaginal tissue biopsies, ISL-TP AM concentration was as follows:

  • 13,500 ± 500 fmol/g tissue after 0.75 mg (n = 3) and
  • 84,000 fmol/g tissue after 5 mg (n = 1).

The comparison of tissue levels of antiretrovirals to benchmark against threshold activity levels is complicated by several factors that need to be accounted for. In Table 3, the above results are compared with previous results with tenofovir diphosphate (TFV-DP) and FTC-TP, accounting for a range of possible ratios of epithelial and inflammatory cells in the biopsy specimens.

TABLE 3. - Comparison of Antiretroviral Uptake in Rectal and Vaginal Tissue Relative to IC50
IC50* Rectal Vaginal
Concentration (fmol/g) Concentration (fmol/106 Cells) Relative to IC50 Concentration (fmol/g) Concentration (fmol/106 Cells) Relative to IC50
ISL-TP 0.75 mg ISL
9.7 fmol/106 cells21 53,700 26–43 2.7–4.4x 13,500 6–11 0.6–1.1x
TFV-DP 300 mg TDF
41.5 fmol/106 cells21 206,000§ 99–165 2.4–4.0x 41,000§ 20–33 0.5–0.8x
FTC-TP 200 mg FTC
113 fmol/106 cells21 8450 4.1–6.8 0.04–0.06x 63,469 31–51 0.3–0.5x
*Only mean values listed for simplicity.
To convert from fmol/g to fmol/106 cells, several assumptions are made as follows: (1) biopsy samples are 10%–30% PBMCs and 70%–90% epithelial cells by mass, (2) PBMCs are 0.2 pL and epithelial cells are ∼1.2 pL, and (3) active compound is evenly distributed among cell types. This leads to a cell count of 1.25 × 109 (10/90), 1.67 × 109 (20/80), and 2.08 × 109 (30/70) cells/g. The tissue concentration is then normalized to fmol/106 cells. It is acknowledged that this oversimplifies the makeup of biopsy specimens and does not account for possible differences between rectal and vaginal specimens. The presence of unaccounted for noncellular connective tissue would effectively increase cellular concentrations for all compounds.
The mean from N = 4 for rectal sample and N = 3 for vaginal sample. SDs (noted in text) omitted here for simplicity.
§The median from N = 4 for rectal sample and vaginal sample is N = 1. For simplicity, only the mean value is used for calculations.29
The median values noted for rectal (N = 8) and vaginal (N = 7) tissue.22
FTC, emtricitabine; FTC-TP, emtricitabine triphosphate; ISL, islatravir; ISL-TP, islatravir-triphosphate; PBMC, peripheral blood mononuclear cells; IC50, the in vitro concentration of drug resulting in 50% inhibition of virus; TDF, tenofovir disoproxil fumarate; TFV-DP, tenofovir diphosphate.

Safety and Tolerability of Islatravir

Seventeen of the 36 participants (47.2%) reported treatment-emergent AEs. AEs were considered by the investigator to be drug-related in 4 participants (11.1%) and included flatulence and headache, each reported by 1 participant in the 0.25 mg group, and anemia and rash, each reported by 1 participant in the 0.75 mg group. No trends were observed between AE incidence and dose. The rash was described as a pink vesicle/blister on the dorsal side of the left ring finger that was noted after 27 days of dosing and resolved in 17 days. Of note, concomitant with the rash, the participant also reported a mild AE of a scratch in the left forearm with the same onset and resolution dates; this was considered to be unrelated to the study drug. One participant had a serious AE of rectal hemorrhage after the rectal biopsy procedure, which was considered to be related to the study procedure but unrelated to the study drug. No deaths, discontinuations due to AEs, or events of clinical interest were reported during the study. The most commonly reported AEs were headache (n = 6), oropharyngeal pain (n = 4), and dizziness (n = 3). All AEs were of mild intensity (defined as subject awareness of sign/symptom but easily tolerated), and all except 1 (anemia) had resolved by the end of the study. There were no AEs related to laboratory assessments or vital signs reported.

DISCUSSION

Islatravir is a novel HIV-1 nucleoside analog in development for the treatment and prevention of HIV-1 infection, with a PK profile that supports a range of dosing schedules. In this study, the safety and PK of islatravir administered QD for up to 6 weeks were assessed to support ongoing clinical evaluations of islatravir QD administration.

As noted above, virologic response is often predicted using the IQ (ratio of drug concentration at Ctrough over the intracellular concentration required for efficacy). The calculated IQ is 5 for wild-type HIV-1 and ≥1 for M184I/V when the trough concentration is maintained at or above ∼0.05 pmol/106 cells. Islatravir has a >4-fold lower in vitro intracellular IC50 for wild-type HIV-1 virus than any approved NRTIs,9 and the IQ for islatravir against wild-type HIV-1 after steady state dosing of 0.25 mg QD is 85.3 (90% confidence interval: 44.8 to 126), which is more than 2 times higher than the IQ achieved by any other marketed NRTI.15 In this trial, the PK threshold of ∼0.05 pmol/106 cells is achieved at 24 hours after one dose of islatravir 0.25 mg and improves with the accumulation of islatravir-TP, exceeding efficacious concentrations in the monotherapy antiviral efficacy trial.10 Therefore, 0.25 mg was selected as the lowest daily dose of islatravir for further study. Based on the results of the current study, the trough threshold of ISL-TP (C24) was reached at every dose tested after the first dose, which supports the potential for antiviral efficacy of islatravir even at doses as low as 0.25 mg.

ISL-TP levels in PBMCs exhibited PK behavior consistent with data obtained from previous single-dose and multiple-dose trials, with Tmax ranging from 4 to 24 hours and an apparent terminal t1/2 ranging from 177 to 209 hours.10 Plasma islatravir and ISL-TP AUC0–24, Cmax, and Cavg values increased with increasing dose in an approximate dose proportional manner across the dose levels tested, similar to previous trials.22 As expected, AUC0–24 and Cavg increased after repeated administration, but GM Cmax values were similar after single and multiple administrations at all 3 dose levels. Islatravir plasma concentrations decreased in a biphasic manner, with an initial rapid phase and a slow terminal phase. The increases in apparent terminal t1/2 with dose may be due to concentrations falling below detection at lower doses, but apparent terminal t1/2 does seem to be extended after multiple dosing. This may be due to redistribution of the parent drug from the PBMCs back into the plasma, as would be expected if ISL-TP is slowly dephosphorylated back to islatravir in PBMCs and is then able to exit the cell into the plasma. The sample size of the current study was small, however, and this hypothesis requires further investigation. Tolerability of islatravir did not seem to be affected by the apparent extended half-life of islatravir in the plasma. GM Ae, CLr, and fe of urine islatravir increased with increasing dose of islatravir, and GM Ae and fe tended to increase with repeated administration within the 0.75- and 5-mg dose levels, whereas GM CLr values seemed similar.

Islatravir is being developed as a component of a treatment regimen for HIV-1 infection but is also being developed as a potential agent for the prevention of HIV-1. The concentration of antiretroviral medications in specific tissues and anatomical sites of potential HIV-1 replication may be relevant to clinical effectiveness, especially for prevention.4 For some antiretroviral agents, there is evidence that antiretroviral drug penetration and exposure may vary between the systemic compartment and sites of HIV-1 transmission such as genital tract tissue,23,24 and there is a level of controversy surrounding whether sufficient tissue concentrations, specifically within rectal and vaginal tissue, are achieved for effective prevention.4 Levels of TFV-DP—the active form of tenofovir disoproxil fumarate—for example, may be lower in the female genital tract than in colorectal tissue.23,24 There are also data demonstrating a correlation between HIV-1 prevention and drug tissue concentrations.25 Not entirely consistent with this hypothesis, however, are studies investigating cabotegravir for the prevention of HIV-1 infection in which effective protection was achieved despite low levels of cabotegravir in genital compartments.26 The results in Table 3, based on the data reported in this study and data from published reports, suggest that both ISL-TP and TFV-DP are likely to be at concentrations above IC50 threshold levels in rectal tissue and close to threshold levels in vaginal tissue, with ISL-TP levels relative to IC50 being slightly higher. Although biopsies were taken from a small subset of participants in the current trial, the findings are encouraging given the importance of achieving efficacious antiviral and protective concentrations of the active form of antiretroviral agents at key potential transmission sites.23

In conclusion, multiple daily dosing of islatravir in adults without HIV-1 infection was generally well tolerated up to 5 mg daily for 6 weeks, with ISL-TP levels in PBMCs above the level projected for efficacy after a single dose as low as 0.25 mg. Together with the finding that IQs of islatravir for both wild-type and NRTI-resistant HIV-1 at low QD and once-weekly doses are substantially higher than those of any NRTIs approved for HIV treatment, and coupled with the long intracellular half-life of ISL-TP, these IQs suggest there is an opportunity for multiple low-dosing options, with the potential for a high barrier to the development of resistance.15

These findings support the evaluation of oral islatravir 0.25, 0.75, and 2.25 mg QD in combination with doravirine 100 mg QD in a phase 2b trial in treatment-naive PLWH. In that trial, participants were switched to islatravir plus doravirine after initiation on a 3-drug regimen of islatravir, doravirine, and lamivudine for 24 weeks. All islatravir doses in combination with doravirine demonstrated sustained viral suppression through 48 weeks of treatment and were generally well tolerated.27 By 96 weeks, a high proportion of participants maintained viral suppression, including 27 of the 30 participants (90%) receiving the selected islatravir dose of 0.75 mg in combination with doravirine.28 A comprehensive phase 3 clinical trial program (NCT04223778, NCT04223791, NCT04233879, and NCT04233216) will investigate the treatment potential of islatravir 0.75 mg and doravirine 100 mg across populations of PLWH.16

ACKNOWLEDGMENTS

The authors thank Deborah Panebianco for statistical and data analysis support; Vanessa Weissler and Sabrina Fox-Bosetti for operational support; Melanie Anderson, Robert Valesky, Li Sun, Iris Xie, Kenneth Willson, and Neal Dube from the bioanalytical group; and the participants and clinical research staff who participated in this study. Medical writing and editorial assistance, under the direction of the authors, were provided by ApotheCom (Yardley, PA) in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by MSD.

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    Keywords:

    HIV; islatravir; multiple dosing; pharmacokinetics

    Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.