Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants.

GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3- to 4-fold under high- and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.

Although current antiretroviral therapies have been successful in markedly reducing morbidity and prolonging survival among individuals with HIV, challenges with emergent resistance, drug‐drug interactions, and intolerability have resulted in the need for newer classes of agents to improve treatment outcomes. , , Maturation inhibitors (MIs) target a viral replication mechanism that is distinct from the existing protease, reverse transcriptase, and integrase inhibitor classes. MIs interfere with one of the final steps of the HIV‐1 life cycle to prevent the formation of infectious viral particles, specifically by blocking protease‐mediated processing of the structural Gag polyprotein.

GSK3640254 (Figure 1) is an MI being developed for HIV‐1 treatment. In vitro studies of GSK3640254 have demonstrated broad‐spectrum potent inhibition across various HIV‐1 subtypes. In phase I studies in healthy participants (NCT03231943, NCT03575962), GSK3640254 was generally well tolerated, with headache reported as the most common adverse event (AE). Pharmacokinetic analysis showed that GSK3640254 was slowly absorbed, with a median time to maximum observed concentration (tmax) of 3.0 hours and an estimated half‐life of approximately 22.6 hours for the 200‐mg dose, supportive of once‐daily dosing. In the phase IIa proof‐of‐concept study in treatment‐naive adults with HIV‐1 (NCT03784079), the GSK3640254 200‐mg dose resulted in an approximately 2‐log10 reduction in plasma HIV‐1 RNA with no noted safety or tolerability concerns. GSK3640254 is an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 and organic anion‐transporting polypeptide 1B3 in vitro. , Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives. , ,

Figure 1

Structure of GSK3640254.

In both phase I and phase IIa proof‐of‐concept studies, GSK3640254 was formulated as a mesylate salt in a capsule. , In planned phase IIb studies, the proposed formulation for GSK3640254 is a mesylate salt in a tablet. Because of the planned formulation change between phase IIa and phase IIb studies, it was critical to determine whether dose adjustments were required. Additionally, as all GSK3640254 completed clinical studies to date have been conducted under moderate‐calorie and ‐fat conditions, it was important to investigate the effect of moderate‐ and high‐fat conditions on the pharmacokinetics and safety of the planned GSK3640254 mesylate tablet formulation in comparison with fasted conditions.

Herein, we report the results from a phase I, 2‐part study in healthy participants assessing the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations as well as the effect of food on the pharmacokinetic and safety profile of the tablet formulation.

Methods

Study Design

This was a phase I, 2‐part, randomized, open‐label, single‐dose, crossover study conducted at 1 center in the United States (PPD, Austin, Texas) to compare the relative bioavailability of GSK3640254 mesylate salt tablet and capsule formulations (part 1) and to assess the effect of food on the GSK3640254 tablet formulation (part 2) in healthy adults (ClinicalTrials.gov identifier, NCT04263142). Part 1 consisted of a screening period (≤28 days before day 1 of treatment) and 2 sequential single‐dose treatment periods separated by a ≥7‐day washout (Figure 2A). Participants were randomized to 1 of 2 GSK3640254 200 mg treatment sequences (capsule‐tablet or tablet‐capsule). Treatments were administered as a single dose given as two 100‐mg capsules or tablets with a moderate‐fat meal 30 minutes before dosing. Part 2 consisted of a screening period (≤28 days before day 1 of treatment) and 3 sequential single‐dose treatment periods separated by a ≥7‐day washout (Figure 2B). Participants were randomized to 1 of 3 treatment sequences with a single dose of GSK3640254 200 mg given as two 100‐mg tablets (moderate‐fat, fasted, and high‐fat conditions) in each treatment period. Participants received either a moderate‐ or high‐fat meal 30 minutes before dosing or fasted overnight for at least 10 hours before dosing and until 4 hours after dosing.

Figure 2

Study design schematics for (A) part 1 and (B) part 2.

The study was conducted in accordance with the International Conference on Harmonization ethical principles of good clinical practice and the Declaration of Helsinki. Written informed consent was obtained from each participant. The protocol and study conduct were approved by an institutional review board (IntegReview IRB, Austin, Texas).

Study Participants

Eligible participants were generally healthy individuals aged 18 to 55 years, and eligible female participants could not be pregnant (confirmed by a negative highly sensitive serum pregnancy test at screening) or able to become pregnant (using a nonhormonal contraceptive method). Additional eligibility criteria included body weight ≥50 kg (men) and ≥45 kg (women), and body mass index between 18.5 and 31.0 kg/m2. Participants were excluded from the study if they had a history of any condition that could affect the absorption, metabolism, or excretion of the study treatment or a history of liver or cardiac disease. Additional exclusion criteria were related to laboratory parameters, including a positive HIV, hepatitis B, or hepatitis C test or alanine aminotransferase >1.5 times the upper limit of normal.

Study Assessments

The primary objective of part 1 was to assess the relative bioavailability of GSK3640254 mesylate tablets and capsules in the presence of a moderate‐fat meal using pharmacokinetic parameters. The primary objective of part 2 was to assess the effect of food on the pharmacokinetics of the tablet formulation. Secondary objectives were to assess the safety and tolerability of GSK3640254 after single oral administration and to characterize pharmacokinetics.

In both parts 1 and 2, blood samples for pharmacokinetic analysis were collected 40 minutes before dosing on day 1 and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 24, 48, 72, and 96 hours after dosing in each treatment period. GSK3640254 concentrations were measured using ultra‐high‐performance liquid chromatography with tandem mass spectrometry. Safety and tolerability were assessed by monitoring and recording AEs, clinical laboratory test results, vital sign measurements, 12‐lead electrocardiogram results, and physical examination findings.

Data Analysis

No formal statistical hypotheses were tested in this study. The sample size calculation was based on a 38% intraparticipant coefficient of variation based on the results from previous pharmacokinetic studies of GSK3640254. Plasma concentrations were summarized descriptively. Pharmacokinetic parameters were calculated by standard noncompartmental methods using Phoenix WinNonlin version 8.0 (Certara, Princeton, New Jersey), based on actual sampling times. Primary plasma pharmacokinetic parameters (area under the plasma concentration–time curve from time 0 extrapolated to infinity [AUC0‐∞], area under the plasma concentration–time curve from time 0 to the last quantifiable concentration [AUC0‐t], maximum observed concentration [Cmax], and tmax) and secondary plasma pharmacokinetic parameters (apparent terminal phase half‐life [t1/2] and apparent oral clearance [CL/F]) were estimated for GSK3640254. Statistics were summarized by treatment for each part of the study. Analyses to compare the relative bioavailability of the tablet formulation of GSK3640254 with the capsule formulation were performed on the natural logarithms of pharmacokinetic parameters AUC0‐∞, AUC0‐t, and Cmax using linear mixed‐effect models with treatment, period, and sequence as fixed effects and participant as a random effect. Effects were estimated, and CIs were obtained for the tablet vs the capsule. Nonparametric analysis was performed to compare the tmax of the tablet formulation with the capsule formulation, and the Hodges‐Lehmann estimate was used to produce the treatment difference. For the food effect, the same mixed‐effects model was evaluated with fixed‐effects terms for treatment (fasted, moderate fat, and high fat), period, and sequence and participant as a random effect. The effect of food on the tmax of the tablet formulation was similarly analyzed for moderate‐fat vs fasted and high‐fat vs fasted conditions. Safety analyses were based on the safety population, defined as all participants who received ≥1 dose of study medication, and were summarized descriptively.

Results

Study Population

Across both studies, 94 participants were screened, and 39 participants (41%) were enrolled. In part 1, 18 participants (men, n = 13; women, n = 5) with a mean (SD) age of 35.8 (9.25) years were randomized to treatment, all of whom completed the study. In part 2, 21 participants (men, n = 12; women, n = 9) with a mean (SD) age of 32.7 (9.01) years were randomized to treatment, 19 (90%) of whom completed the study. One participant (5%) was withdrawn because of an AE, and 1 (5%) was withdrawn as a result of physician's decision. Baseline demographics from participants in parts 1 and 2 are summarized in Table 1.

Table 1

Baseline Demographics of the Study Populations for Part 1 and Part 2

Parameter	Part 1 (N = 18)	Part 2 (N = 21)
Age, y, mean (SD)	35.8 (9.25)	32.7 (9.01)
Sex, n (%)
Female	5 (28)	9 (43)
Male	13 (72)	12 (57)
BMI, kg/m2, mean (SD)	27.2 (2.97)	26.5 (3.51)
Height, cm, mean (SD)	172 (11.7)	170 (10.1)
Weight, kg, mean (SD)	80.8 (16.5)	76.8 (13.7)
Ethnicity, n (%)
Hispanic or Latino	8 (44)	6 (29)
Not Hispanic or Latino	10 (56)	15 (71)
Race, n (%)
White	10 (56)	12 (57)
Black or African American	6 (33)	9 (43)
American Indian or Alaskan Native	1 (6)	0
Native Hawaiian or other Pacific Islander	1 (6)	0

BMI, body mass index; SD, standard deviation.

Pharmacokinetic Results

In part 1, mean peak (Cmax) and total (AUC0‐∞ and AUC0‐t) plasma exposures after administration of the GSK3640254 tablet formulation were not meaningfully different compared with the capsule formulation in the presence of a moderate‐fat meal (Figure 3). Pharmacokinetic data from the summary statistics and analysis of variance models for part 1 are shown in Tables 2 and 3, respectively. With both formulations, plasma concentrations declined in a monophasic manner. Geometric least squares (LS) mean ratios between the formulations were 0.998, 1.00, and 1.09 for AUC0‐∞, AUC0‐t, and Cmax, respectively. The median (90%CI) difference in tmax for the tablet formulation compared with the capsule formulation was −1.28 hours (−2.00 to −0.283). Mean estimates for t1/2 and CL/F were similar for both formulations.

Figure 3

Mean (SD) GSK3640254 plasma concentration–time plots by treatment in part 1: (A) linear and (B) semilogarithmic. Dashed line represents lower limit of quantification (3.00 ng/mL). SE, standard error.

Table 2

Part 1 Summary of GSK3640254 Plasma Pharmacokinetic Parameters by Treatment

Parameter	Capsule 200 mg (N = 18)	Tablet 200 mg (N = 18)
AUC0‐∞, μg • h/mL
Geometric mean (%CVb)	36.9 (42.7)	36.9 (40.3)
Arithmetic mean (SD)	39.6 (13.9)	39.4 (13.9)
AUC0‐t, μg • h/mL
Geometric mean (%CVb)	33.7 (41.1)	33.8 (40.2)
Arithmetic mean (SD)	35.9 (11.8)	36.1 (12.5)
Cmax, μg/mL
Geometric mean (%CVb)	1.20 (33.4)	1.31 (45.3)
Arithmetic mean (SD)	1.26 (0.369)	1.43 (0.577)
tmax, h
Median (range)	5.00 (3.00‐12.0)	4.00 (2.50‐6.00)
t1/2, h
Geometric mean (%CVb)	26.2 (17.6)	26.2 (17.2)
Arithmetic mean (SD)	26.6 (4.68)	26.5 (4.59)
CL/F
Geometric mean (%CVb)	5.41 (42.7)	5.42 (40.3)
Arithmetic mean (SD)	5.94 (3.23)	5.84 (2.45)

AUC0‐∞, area under the plasma concentration–time curve from time 0 extrapolated to infinity; AUC0‐t, area under the plasma concentration–time curve from time 0 to last quantifiable concentration; CL/F, apparent oral clearance; Cmax, maximum observed concentration; CVb, between‐participant coefficient of variation; SD, standard deviation; t1/2, apparent terminal phase half‐life; tmax, time to Cmax.

Table 3

Part 1 Statistical Analysis of GSK3640254 Pharmacokinetic Parameters: Analysis of Variance

Parameter	Geometric LS Mean	Ratio	90%CI	Intraparticipant CV
AUC0‐∞, μg • h/mL
Capsule (n = 18)	36.9	0.998	0.926 to 1.08	12.9
Tablet (n = 18)	36.9
AUC0‐t, μg • h/mL
Capsule (n = 18)	33.7	1.00	0.932 to 1.08	12.5
Tablet (n = 18)	33.8
Cmax, μg/mL
Capsule (n = 18)	1.20	1.09	0.989 to 1.21	17.4
Tablet (n = 18)	1.31
tmax, h
Capsule (n = 18)	5.00 b	−1.28 c	−2.00 to −0.283	–
Tablet (n = 18)	4.00 b

AUC0‐∞, area under the plasma concentration–time curve from time 0 extrapolated to infinity; AUC0‐t, area under the plasma concentration–time curve from time 0 to last quantifiable concentration; Cmax, maximum observed concentration; CV, coefficient of variation; LS, least squares; tmax, time to Cmax.

An analysis of variance with treatment, period, and sequence as fixed effects and participant as a random effect was performed on the natural ln‐transformed parameters AUC0‐∞, AUC0‐t, and Cmax.

Median.

Median difference.

In part 2, when the GSK3640254 tablet formulation was administered in the presence of a moderate‐ or high‐fat meal, mean peak (Cmax) and total (AUC0‐∞ and AUC0‐t), plasma exposures were higher than under fasted conditions (Figure 4). Pharmacokinetic data from the summary statistics and analysis of variance models for part 2 are shown in Tables 4 and 5, respectively. Six participants who received GSK3640254 under fasted conditions had predose plasma concentrations >5% of the Cmax value for the treatment and were excluded from summary statistics and mean concentration‐time plots. Mean Cmax values under moderate‐ and high‐fat conditions were ≈4‐ and 3‐fold higher, respectively, than under fasted conditions. Moderate‐ and high‐fat conditions increased mean AUC0‐∞ by ≈3.1‐ and 2.7‐fold, respectively, compared with fasted conditions. Geometric LS mean ratios between moderate‐fat and fasted conditions were 2.93, 3.15, and 4.10 for AUC0‐∞, AUC0‐t, and Cmax, respectively. Comparing high‐fat and fasted conditions, geometric LS mean ratios were 2.59, 2.79, and 3.08 for AUC0‐∞, AUC0‐t, and Cmax, respectively. For all treatment conditions, plasma concentrations declined in a monophasic manner. Median (90%CI) difference in tmax was 0.500 (−0.750 to 1.98) and 1.50 hours (0.250 to 2.75) for the moderate‐ and high‐fat conditions, respectively, compared with the fasted condition. Mean estimates for t1/2 were similar across treatment conditions, while the mean estimate for CL/F was >60% lower under moderate‐ or high‐fat conditions than under fasted conditions.

Figure 4

Mean (SD) GSK3640254 plasma concentration–time plots by treatment in part 2: (A) linear and (B) semilogarithmic. Dashed line represents lower limit of quantification (3.00 ng/mL).

Table 4

Part 2 Summary of GSK3640254 Plasma Pharmacokinetic Parameters by Treatment

Parameter	Moderate Fat (N = 20)	Fasted (N = 19) a	High Fat (N = 21)
AUC0‐∞, μg • h/mL b
Geometric mean (%CVb)	41.0 (42.2)	13.5 (58.2)	36.9 (35.9)
Arithmetic mean (SD)	44.1 (16.3)	15.7 (10.9)	39.1 (13.6)
AUC0‐t, μg • h/mL c
Geometric mean (%CVb)	37.9 (41.5)	11.4 (65.6)	34.1 (34.9)
Arithmetic mean (SD)	40.7 (15.0)	13.5 (9.5)	36.0 (11.9)
Cmax, μg/mL c
Geometric mean (%CVb)	1.43 (35.6)	0.354 (84.4)	1.08 (38.6)
Arithmetic mean (SD)	1.51 (0.512)	0.449 (0.351)	1.16 (0.434)
tmax (hour) c
Median (range)	5.00 (2.00–8.00)	4.00 (2.03–24.0)	5.00 (1.50–12.0)
t1/2 (hour) b
Geometric mean (%CVb)	24.9 (18.0)	25.7 (12.7)	24.8 (15.7)
Arithmetic mean (SD)	25.3 (5.13)	25.9 (3.33)	25.1 (4.18)
CL/F b
Geometric mean (%CVb)	4.88 (42.2)	14.9 (58.2)	5.42 (35.9)
Arithmetic mean (SD)	5.30 (2.37)	16.6 (7.44)	5.74 (2.01)

AUC0‐∞, area under the plasma concentration‐time curve from time 0 extrapolated to infinity; AUC0‐t, area under the plasma concentration–time curve from time 0 to last quantifiable concentration; CL/F, apparent oral clearance; Cmax, maximum observed concentration; CVb, between‐participant coefficient of variation; SD, standard deviation; t1/2, apparent terminal phase half‐life; tmax, time of Cmax.

Six participants who received GSK3640254 under fasted conditions had predose plasma concentrations >5% of Cmax; these participants were excluded from summary statistics and statistical analyses.

n = 10, fasted condition.

n = 13, fasted condition.

Table 5

Part 2 Statistical Analysis of GSK3640254 Pharmacokinetic Parameters: Analysis of Variance

Parameter	Geometric LS Mean	Ratio b	90%CI	Intraparticipant CV
AUC0‐∞, μg • h/mL
Fasted (n = 19) c , d	14.2	–	–	27.5
Moderate fat (n = 20)	41.6	2.93	2.37 to 3.61
High fat (n = 21)	36.9	2.59	2.10 to 3.20
AUC0‐t, μg • h/mL
Fasted (n = 19) c , e	12.2	–	–	29.5
Moderate fat (n = 20)	38.5	3.15	2.59 to 3.82
High fat (n = 21)	34.1	2.79	2.29 to 3.38
Cmax, μg/mL
Fasted (n = 19) c , e	0.351	–	–	36.1
Moderate fat (n = 20)	1.44	4.10	3.24 to 5.18
High fat (n = 21)	1.08	3.08	2.44 to 3.89
tmax, h f
Fasted (n = 19) c	4.00 g	–	–	–
Moderate fat (n =  20)	5.00 g	0.500 h	−0.750 to 1.98
High fat (n = 21)	5.00 g	1.50 h	0.250 to 2.75

AUC0‐∞, area under the plasma concentration‐time curve from time 0 extrapolated to infinity; AUC0‐t, area under the plasma concentration‐time curve from time 0 to last quantifiable concentration; Cmax, maximum observed concentration; CV, coefficient of variation; LS, least squares; tmax, time to Cmax.

An analysis of variance with treatment, period, and sequence as fixed effects and participant as a random effect was performed on the natural ln‐transformed parameters AUC0‐∞, AUC0‐t, and Cmax.

Ratio compared with fasted conditions.

Six participants who received GSK3640254 under fasted conditions had predose plasma concentrations >5% of Cmax; these participants were excluded from summary statistics and statistical analyses.

n = 10, fasted condition.

n = 13, fasted condition.

n = 13, all conditions.

Median.

Median difference.

Safety Results

In part 1, 1 (6%) participant experienced an AE of mild eye irritation after administration of the GSK3640254 tablet formulation (Table 6). This event was assessed as not related to the study treatment by the investigator. No AEs were reported after administration of the GSK3640254 capsule formulation.

Table 6

Summary of All Adverse Events

	Part 1		Part 2
Preferred Term, n (%)	Capsule 200 mg (N = 18)	Tablet 200 mg (N = 18)	Moderate Fat (N = 20)	Fasted (N = 19)	High Fat (N = 21)
Any event	0	1 (6)	0	0	5 (24)
Eye disorders
Eye irritation	0	1 (6)	0	0	0
Gastrointestinal disorders
Diarrhea a	0	0	0	0	2 (10)
Abdominal distention a	0	0	0	0	1 (5)
Psychiatric disorders
Anxiety	0	0	0	0	1 (5)
Reproductive system and breast disorders
Dysmenorrhea	0	0	0	0	1 (5)
Skin and subcutaneous tissue disorders
Rash maculopapular a , b	0	0	0	0	1 (5)

At each level of participant summarization, a participant was counted once if the participant reported ≥1 events. Adverse events that occurred after last treatment date and time + 5 days were not included.

Drug related.

Led to participant withdrawal from study.

In part 2, 5 (24%) participants experienced AEs, all of which occurred after administration of GSK3640254 tablets under high‐fat conditions. All AEs were considered mild. The most commonly reported AE was diarrhea (n = 2; 10%). Two (10%) participants reported 3 AEs that were considered related to the study treatment: 1 participant experienced abdominal distention (resolved 2 hours after onset) and diarrhea (resolved 1 minute after onset), and the other participant experienced an AE of rash maculopapular, leading to withdrawal from the study. The event was resolved ≈11 days after onset. There were no serious AEs or clinically relevant trends in laboratory values, vital sign measurements, or electrocardiograms reported in part 1 or 2 of the study.

Discussion

In this phase I, 2‐part trial, the relative bioavailability of the GSK3640254 capsule and tablet formulations and the effect of food on GSK3640254 pharmacokinetics were evaluated in healthy participants. Results demonstrated that the tablet formulation of GSK3640254 planned for the phase IIb study was comparable to the capsule formulation used in prior phase I and phase IIa clinical studies, with no noted safety or tolerability findings.

After administration of a single dose of GSK3640254 200 mg under moderate‐fat conditions, mean peak and total plasma exposures were similar between the capsule and tablet formulations (geometric mean ratios between 0.998 and 1.09), indicating good relative bioavailability.

A food effect was expected given the structural similarity to a prior MI that also needed administration with food to achieve adequate exposure. Relative to the fasted state, concomitant intake of food with oral drug formulations can significantly affect the rate and extent of drug absorption and bioavailability. Such variations in drug exposures are generally due to food‐mediated changes in physiological processes such as fluctuations in gastrointestinal pH, increase in luminal fluids, release of bile salts, increase in splanchnic blood flow, and inhibition of transporters. , , Compared with administration under fasted conditions, administration of GSK3640254 under high‐ and moderate‐fat conditions resulted in a 3‐ to 4‐fold increase in mean peak and total plasma exposures (geometric mean ratios between 2.59 and 4.10). This increase in plasma exposure with the coadministration of food is similar to observations from another MI study. Relative to fasted conditions, increases in peak (Cmax) and total (AUC0‐∞ and AUC0‐t) plasma exposures appeared to be greater under moderate‐fat conditions (geometric mean ratios between 2.93 and 4.10) than high‐fat conditions (geometric mean ratios between 2.59 and 3.08). However, this study was not specifically designed to compare increases in exposures between moderate‐ and high‐fat meals. Moderate‐ and high‐fat conditions slightly delayed tmax relative to fasted conditions (median difference of 0.500 and 1.50 hours, respectively). Median tmax values for GSK3640254 were similar regardless of formulation or meal content (4‐5 hours).

A potential limitation of this study is the reduced precision in the statistics from part 2 due to the exclusion of participants from the fasted treatment group with predose plasma concentrations >5% of the Cmax value for the treatment.

Overall, the results from this study confirmed the suitability of the GSK3640254 tablet formulation for the phase IIb study (NCT04493216).

Conflicts of Interest

M.J., S.R.J., and M.L. are employees of ViiV Healthcare and may own stock in GlaxoSmithKline (GSK). A.M., V.B., and J.Z. are employees of and may own stock in GSK. T.P.D. was an employee of GSK during the conduct of the study and may own stock in GSK.

Funding

This study was funded by ViiV Healthcare.