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Antimicrobial Agents and Chemotherapy, December 2007, p. 4284-4289, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00716-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Safety and Pharmacokinetics of GSK364735, a Human Immunodeficiency Virus Type 1 Integrase Inhibitor, following Single and Repeated Administration in Healthy Adult Subjects

Y. Sunila Reddy,^1, Sherene S. Min,^1* Julie Borland,¹ Ivy Song,¹ Jiang Lin,¹ Sandra Palleja,² and William T. Symonds^1,

GlaxoSmithKline, Research Triangle Park, North Carolina Shionogi USA, Inc., Florham Park, New Jersey

Received 1 June 2007/ Returned for modification 23 July 2007/ Accepted 30 September 2007

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Emerging viral multiclass drug-resistant strains and long-term toxicities warrant development of new classes of antiretroviral therapies. Human immunodeficiency virus (HIV) integrase is one of the three key enzymes of the pol gene of HIV and is involved in the integration of HIV DNA into the host chromosomal DNA. This enzyme is an attractive target for HIV therapy because it is essential for HIV replication, and, unlike protease and reverse transcriptase, this enzyme does not have a cellular homologue (1). Integration, catalyzed via integrase, requires two metal-dependent consecutive steps in the viral replication cycle: 3' processing and strand transfer (5).

GSK364735 is a two-metal-binding HIV integrase strand transfer inhibitor under development within a joint venture between GlaxoSmithKline and Shionogi. GSK364735 exhibited potent in vitro inhibition of recombinant HIV integrase and viral replication in cell-based assays with 50% inhibitory concentrations (IC₅₀) at single-digit nanomolar (nM) levels. The in vitro IC₅₀ of GSK364735 in a peripheral blood lymphocyte assay with HIV-1 strain Ba-L was 1.2 nM. A protein-adjusted (PA) IC₅₀ value of 42 nM was calculated based on a shift in the IC₅₀ value for GSK364735 in 100% human serum, and the PA IC₉₀ (four times the IC₅₀) was 168 nM (0.062 µg/ml) (R. G. Ferris and R. J. Hazen, unpublished data).

Preclinical pharmacokinetic (PK) and in vitro metabolism and protein binding studies have been conducted. Following single intravenous administration to rats, dogs, and monkeys, GSK364735 has a low-to-moderate clearance (percentages of liver blood flow: rats, 5.8%; dogs, 27.8%; monkeys, 4.6%) and a rapid terminal elimination half-life (t_1/2) ranging from 1.5 to 3.9 h. Oral bioavailabilities of various GSK364735 formulations in rats, dogs, and monkeys ranged from 6 to 100%. In vivo studies using animals (rats and monkeys) suggested that metabolism is the major route of elimination for GSK364735 and that renal excretion of GSK364735 is minimal. In vitro studies using human hepatocytes and expressed cytochrome P450 (CYP) enzymes indicate that metabolism through glucuronidation by UDP-glucuronosyltransferase (UGT) and oxidation by CYP1A2 are likely the major routes of elimination for GSK364735. Evaluations of cultured human hepatocytes suggest a lack of CYP/UGT induction potential by GSK364735. GSK364735 is also substrate of P-glycoprotein with high passive membrane permeability. It is 99% bound to human plasma proteins, as assessed by in vitro equilibrium dialysis.

The objectives of this study were to determine single- and repeated-dose safety, tolerability, and PK of GSK364735 in healthy subjects. The effect of a moderate-fat/calorie meal on GSK364735 exposure following single-dose administration of GSK364735, a Biopharmaceutics Classification System class 2 compound (low solubility and high permeability), was also determined using a single-sequence crossover design approach.

(These data were presented in part at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, February 2007.)

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study design. This was a double-blind, randomized, parallel, placebo-controlled, single- and repeated-dose escalation study with healthy subjects. Healthy, HIV-seronegative men and women of non-child-bearing potential between the ages of 18 and 55 with a body mass index (BMI) between 18.5 and 29.9 kg/m² (inclusive) were recruited based on the investigator's review of the subjects ' medical histories, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECG), and 24-hour Holter data. Subjects were excluded for abnormal vital signs; regular alcohol, tobacco, or illicit drug use; hepatitis B or C virus or HIV infection; recent receipt of another investigational product; abnormal laboratory parameters; clinically significant cardiac arrhythmias; or abnormal corrected QT values. Concomitant medications, including prescription, nonprescription, vitamin, and herbal products, were excluded, with the exception of acetaminophen. All subjects provided written informed consent, and the protocol was approved by the Institutional Review Board of Covance in Madison, WI.

Doses were selected based on allometric scaling of animal PK data (3) and consideration of toxicology of no-observed-adverse-effect-level exposures. GSK364735 was available as 10-, 50-, and 200-mg tablets. Doses were escalated in a sequential fashion, and projected doses were modified upon review of actual PK and safety data from previous dosing cohorts. The study design is shown in Table 1. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug, 2 receiving a placebo) received single escalating doses of 50 mg, 100 mg, 200 mg, or 400 mg in a fasted state. Food effect was assessed at the 200-mg dose in the same cohort that received 200 mg in a fasted state. Based on the observed effect at the 200-mg and 400-mg doses in a fasted state, food effect was also assessed at the 400-mg dose in a different cohort of subjects than those who received 400 mg fasted. Subjects received their doses with a standard moderate-fat breakfast (30% fat calories). They consumed the meal within 25 min, and GSK364735 was administered within 5 min of meal completion. In part B, five individual cohorts (8 receiving the active drug, 2 receiving a placebo) were recruited for sequential repeated-dose escalation of 50 mg, 100 mg, and 200 mg every 12 h (q12h), 400 mg q24h, and 200 mg q8h for 8 days. On days 1 and 8, only the morning dose was administered. All doses were administered with a standard moderate-fat meal (30% fat calories). Subjects were admitted to the research unit the evening prior to dosing and remained there until the 48-h postdose study assessments were completed in part A and 24-h postdose study assessments were completed in part B. All doses were observed by the clinical staff.

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TABLE 1. Study design

Safety assessments. Vital signs (VS), 12-lead ECG, hematology, clinical chemistry, urinalysis, and clinical adverse events (AEs) were collected prior to dosing, during the dosing period, and through the follow-up period (7 to 14 days after the final dose of GSK364735). Laboratory data were obtained 24 and 48 h after single dosing and on days 3, 5, and 8 during repeated dosing. Physical examinations were performed prior to dosing and prior to discharge for each treatment period. VS and ECGs were assessed frequently during single-dose administration and daily (VS) and on days 1, 4, and 8 (ECGs) during repeated-dose administration. Continuous three-lead telemetry monitoring was employed for a 24-hour period after single-dose administration and for 24-hour periods intermittently during repeated-dose administration. Research staff inquired about AEs daily with open-ended questions, and AEs occurring during the trial were evaluated by the investigator for relationship to the study drug and graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS criteria (DAIDS 2004).

PK assessments. Serial blood samples were collected to determine plasma concentrations of GSK364735.

(i) Part A, single-dose escalation. Samples were collected prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h postdose.

(ii) Part B, repeated-dose escalation. On day 1, only one dose was administered, i.e., the morning dose, and PK samples were collected prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 h postdose. On days 3 through 7, trough PK samples were collected each day just prior to the morning dose. On day 8 of the study, PK samples were collected prior to the morning dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 h after the morning dose. Blood samples were processed within 1 h of collection, and plasma was extracted by centrifugation and stored at –70°C prior to analyses.

Bioanalysis. Following extraction from plasma by protein precipitation, GSK364735 concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method (PE Sciex Analyst, version 1.1, and SMS2000, version 1.4) using TurboIonspray and multiple-reaction monitoring at GlaxoSmithKline. [¹³C, ²H₃]GSK364735 was used as an internal standard. The validated linear concentration range was 5 to 5,000 ng/ml. Three concentrations of quality control (QC) samples were included in each run at 20, 400, and 4,000 ng/ml. Based on the results of the analysis of these QC samples, the bias ranged from –7.6 to 0.3%. The within-run and between-run precisions were less than or equal to 5.6% and 6.1%, respectively.

PK analysis. Plasma GSK364735 PK parameters following single- and repeated-dose administration were determined by noncompartmental analysis of individual concentration-actual time data using WinNonLin Professional, version 4.1 (Pharsight Corporation, Mountain View, CA) for extravascular administration (model 200).

The following plasma PK parameters were calculated for each treatment, when possible: for the single-dose escalation and day 1 of the repeated-dose escalation, the area under the plasma concentration-time profile extrapolated to infinity (AUC_0-) and the area under the plasma concentration-time profile from 0 to t hours postdose (AUC_0-t, for the repeated-dose escalation), where t is 8, 12, and 24 h for the q8h, q12h, and q24h dosing regimens, respectively; the maximum observed plasma concentration (C_max); the time of maximum observed plasma concentration (T_max); the terminal elimination phase rate constant (_z); t_1/2, determined as ln 2/_z; and the apparent oral clearance (CL/F); and for day 8 of the repeated-dose escalation, the area under the plasma concentration-time profile during one dosing interval (AUC_0-); C_max; T_max; observed minimum concentration (C_min); concentration at the end of the dosing interval (C); the accumulation ratio, which is defined as the day 8 AUC_0- divided by the day 1 AUC_0-t; the time-invariance ratio, which is defined as the day 8 AUC_0- divided by the day 1 AUC_0-; _z; t_1/2; and CL/F. Actual elapsed time from dosing was used to estimate all individual PK parameters. The AUC was determined using the linear-up-log-down trapezoidal rule. The _z was estimated using only those data points judged to describe the terminal log-linear decline. The _z and other parameters that rely on _z (e.g., t_1/2 and AUC_0-) were accepted only if a minimum of three data points were used to estimate _z and the duration of time over which _z was estimated was at least twice the subsequently estimated t_1/2.

Statistical analysis. Sample size was based on feasibility. A sample size of 10 subjects (8 receiving GSK364735 and 2 receiving the placebo) per dose group should be sufficient to provide useful safety and PK data for a first-time-in-humans study. Plasma GSK364735 PK parameters were summarized by treatment using descriptive statistics. Dose proportionality of plasma GSK364735 PK parameters was assessed following single-dose administration (AUC_0-, AUC_0-t, C_max, concentration at 12 h [C₁₂], and C₂₄) and repeated-dose administration (AUC_0-, C_max, and C) using the power model by the linear regression of the log-transformed PK parameter on the log-transformed dose. The point estimate of ß, the slope for the log of the dose, and the corresponding 90% confidence interval (CI) were obtained separately for the single-dose escalation and on days 1 and 8 of the repeated-dose escalation. For the repeated-dose assessment, only q12h regimens were included. A value of ß near 1 implied dose proportionality. Secondary analysis of dose proportionality was performed by pairwise analysis of variance (ANOVA).

The effect of food on the plasma GSK364735 PK parameters (AUC_0-, AUC_0-t, C_max, and C₁₂) at selected single doses of GSK364735 was evaluated by ANOVA. PK parameters were log transformed prior to statistical analysis, and the results were expressed as ratios on the original scale. The food effect was estimated by the test-to-reference treatment ratios of geometric least-square (GLS) means and the corresponding 90% CIs.

For the repeated-dose escalation, accumulation ratio (R) and time invariance ratio were assessed using ANOVA. PK parameters were log transformed prior to statistical analysis, and the results were expressed as ratios on the original scale. R was estimated from the ratio of the GLS means of AUC_0-, C_max, and C on day 8 to AUC_0-8, AUC_0-12, or AUC_0-24; C_max, and C₈, C₁₂, or C₂₄ on day 1 and the corresponding 90% CI for each dose group. AUC_0-8 and C₈ for q8h dosing, AUC_0-12 and C₁₂ for q12h dosing, and AUC_0-24 and C₂₄ for q24h dosing were used in the calculation of R. The time invariance ratio was estimated from the ratio of the GLS means of AUC_0- on day 8 to AUC_0- on day 1 and the corresponding 90% CI for each dose group. Achievement of plasma GSK364735 steady-state concentrations was assessed by calculating the point estimate and corresponding 90% CI for the slope of the linear regression of log-transformed day 2 to 8 pre-morning dose concentrations versus day by dose group. The analysis was repeated, dropping the earliest day, until it was either shown that steady state was achieved or only days 7 and 8 were included in the model. To claim that steady state was reached, the predose concentration slope estimate had to be close to zero or the 90% CI for the slope estimate had to include zero. All statistical analyses were performed using SAS, version 8.2 (SAS Institute, Cary, NC).

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Demographics. (i) Single-dose escalation. A total of 30 subjects were enrolled and received at least one dose of the investigational product, and 29 subjects completed the study. The majority of subjects were male (25 subjects; 83%) and white. Three subjects (10%) were African-American, one subject (3%) was Asian, and one subject (3%) was of Arabic/North African heritage. The median (range) age, weight, height, and BMI were 44 years (19 to 55 years), 77 kg (61 to 105 kg), 176 cm (157 to 189 cm), and 26.2 kg/m² (20.5 to 29.6 kg/m²), respectively.

(ii) Repeated-dose escalation. A total of 49 subjects were enrolled and received at least one dose of the investigational product, and 47 subjects completed the study. The majority of subjects were male (46 subjects; 94%). Forty-two subjects (86%) were white, 4 subjects (8%) were African-American, 2 subjects (4%) were Asian, and 1 subject (2%) was of native Hawaiian/pacific islander heritage. The median (range) age, weight, height, and BMI were 24 years (18 to 55 years), 78 kg (55 to 104 kg), 176 cm (154 to 196 cm), and 25.4 kg/m² (20.2 to 30.1 kg/m²), respectively.

Safety and tolerability. (i) Single-dose escalation. GSK364735 was well tolerated following single doses of 50 mg to 400 mg. One subject, who had received placebo, was withdrawn from the study drug prior to dosing in the third period due to an abnormal lipase value (241.0 U/liter). A repeat lipase value was 92 U/liter, the amylase value was normal, and the subject had no abdominal complaints. Few subjects (two or less) reported any AEs for each active dosing cohort (n = 8) of GSK364735, with the exception of GSK364735 at 200 mg coadministered with food (five of eight subjects). The most frequently reported AEs with GSK364735 were application site erythema (3/25, 12%) and erythema (3/25, 12%), related primarily to ECG electrode placement and irritation at venipuncture sites, respectively (Table 2). As few AEs were reported, no dose-related trends in AEs were evident. All AEs were considered to be mild in intensity with the exception of one moderate headache, which was considered related to the study drug (GSK364735 at 200 mg coadministered with food) by the investigator. One subject reported drug-related AEs (diarrhea, flatulence, headache) during administration of GSK364735 at 200 mg with food. No severe or serious AEs were reported, and no subjects withdrew due to an AE.

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TABLE 2. Summary of commonly reported AEs during single-dose administration

No dose-related or clinically significant changes in hematology or clinical chemistry values were observed during the single-dose escalation. There were no clinically significant changes in vital signs, 12-lead ECGs, or continuous telemetry monitoring.

(ii) Repeated-dose escalation. GSK364735 was well tolerated at total daily doses of 100 mg to 600 mg administered for up to 8 days. Two subjects withdrew due to personal reasons unrelated to safety. The most commonly reported AEs with GSK364735 were application site erythema related to ECG electrode placement, headache, and dizziness (Table 3). All AEs were mild except for moderate syncope related to a venipuncture (n = 1) and viral gastroenteritis (n = 3). None of these moderate AEs were considered related to study drug by the investigator. No dose-related trends in AEs were evident. Few drug-related AEs were reported (Table 3), and the most common were headache (4/40, 10%) and dizziness (2/40, 5%). No severe or serious AEs were reported, and no subjects withdrew due to an AE.

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TABLE 3. Summary of commonly reported AEs during repeated-dose administration

With the exception of mild median increases in low-density lipoprotein (LDL) cholesterol during GSK364735 repeated dosing, no other dose-related or clinically significant changes in hematology or clinical chemistry values were observed during the repeated-dose escalation. Median LDL values increased slightly from day –1 to day 8 (0.5 to 9.5 mg/dl) during all GSK364735-containing repeated-dose treatments without similar increases during repeated-dose placebo (–2.0 mg/dl). These LDL increases did not appear to be dose related. There were no clinically significant changes in vital signs, 12-lead ECG, or continuous telemetry monitoring.

GSK364735 PK. (i) Single-dose escalation. The GSK364735 PK parameters are shown in Table 4, and the median plasma concentration-time profiles are shown in Fig. 1. Under fasted conditions, GSK364735 was readily absorbed following single-oral-dose administration, with the maximum concentration achieved between 0.75 and 5.0 h postdose, and the plasma concentration declined in a biexponential manner after reaching C_max. The t_1/2 of GSK364735 was estimated to be 3 to 7 h. Plasma exposure (AUC and C_max) of GSK364735 increased less than proportionally as dose increased and appeared to reach a plateau at 100- to 200-mg doses.

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TABLE 4. PK parametersa following single-dose administration

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FIG. 1. Median GSK364735 concentration-time profiles following single-dose administration (linear and semilog scales).

Food effect was assessed at 200-mg and 400-mg doses. A moderate-fat meal increased GSK364735 AUC_0-, C_max, and C₁₂ by 91%, 24%, and 308%, respectively, and prolonged T_max at the 200-mg dose. Large intersubject variability was observed in GSK364735 PK parameters, with the coefficient of variability between subjects (%CVb) ranging from 20% to 115%.

(ii) Repeated-dose escalation. The day 1 and day 8 GSK364735 PK parameters are shown in Tables 5 and 6, and the day 8 median plasma concentration time profiles are shown in Fig. 2. Plasma exposure (AUC and C_max) of GSK364735 on day 1 of the repeated-dose escalation increased more than proportionally as dose increased from 50 mg to 100 mg and then increased less than proportionally as dose increased further. The average t_1/2 was approximately 3 to 4 h across different dose levels. Following repeated-dose administration, plasma GSK364735 concentrations reached steady state by 6 or 7 days of dosing based on statistical analyses of the slope and visual inspection. Steady-state plasma exposure of GSK364735 increased proportionally as dose increased from 50 mg to 100 mg and then increased less than proportionally as dose increased further.

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TABLE 5. PK parametersa following single- and repeated-dose administration on day 1

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TABLE 6. PK parametersa following single- and repeated-dose administration on day 8

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FIG. 2. Median GSK364735 concentration-time profiles following repeated-dose administration (linear and semilog scales). EC90, 90% effective concentration.

Results of the statistical analysis showed that the geometric mean (90% CI) R values for 50 mg q12h, 100 mg q12h, 200 mg q12h, 400 mg q24h, and 200 mg q8h were 1.57 (1.30 to 1.90), 1.14 (0.95 to 1.38), 1.21 (0.67 to 2.22), 0.86 (0.48 to 1.55), and 1.04 (0.61, 1.78), respectively. The time invariance ratios were 1.41 (1.15 to 1.73), 1.06 (0.88 to 1.28), 0.88 (0.48 to 1.65), 0.81 (0.46 to 1.45), and 0.59 (0.37 to 0.95) for 50 mg q12h, 100 mg q12h, 200 mg q12h, 400 mg q24h, and 200 mg q8h, respectively.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This was the first study that assessed the safety, tolerability, and plasma PK of GSK364735. Single doses ranged from 50 mg to 400 mg, and repeated doses ranged from 50 mg to 200 mg q12h, 400 mg q24h, and 200 mg q8h for 8 days, in combination with food to healthy subjects. GSK364735 was safe and well tolerated across all doses for single- and repeated-dose administration in this study. Of the few AEs that did occur, most were mild in intensity, and no severe or serious AEs were reported. One subject reported drug-related AEs (diarrhea, flatulence, headache) during 200-mg single-dose administration of GSK364735 with food. This gastrointestinal intolerance may have been related to concomitant dosing with food. During repeated-dose administration, the most common drug-related AEs were headache and dizziness. These neurologic symptoms may have been related to confinement in the clinical unit for 9 days and caffeine restriction. Causality by GSK364735 cannot be excluded. Mild median LDL cholesterol increases were noted during repeated-dose GSK364735 administration but not during placebo administration. Due to the small sample sizes, these effects may have been due to the variability of cholesterol values or related to GSK364735. With the exception of these mild LDL cholesterol increases during repeated-dose administration, no clinically significant trends in laboratory abnormalities, vital signs, 12-lead ECGs, or telemetry monitoring were noted.

Following single doses, GSK36473735 was readily absorbed, reaching the C_max between 0.75 and 5.0 h postdose (fasted conditions). A moderate-fat meal increased GSK364735 exposure and prolonged T_max; however, the effect of food seemed dose dependent, as plasma GSK364735 AUC_0- increased by 91% for the 200-mg dose and increased by 28% for the 400-mg dose. Median T_max increased from 2.5 h to 4.0 h at the 200-mg dose and from 2.2 h to 7.0 h at the 400-mg dose. These dose-dependent food effects may be attributed to large PK variability, small sample size, and solubility-limited absorption.

Statistical analysis of steady-state results showed that, following repeated-dose administration of GSK364735, the plasma concentrations of GSK364735 reached steady state after 6 or 7 days of dosing. This was inconsistent with the estimated short t_1/2s of 3 to 7 h across different dose levels. There was moderate accumulation of GSK364735 exposure for q12h dosing, but no accumulation was observed for q24h or q8h dosing. The accumulation ratios for AUC, C_max, and C following q12h dosing are higher than predicted based on estimated t_1/2. Such a discrepancy between achievement of steady state, accumulation, and estimated short half-life is likely due to an underestimation of the true t_1/2 of GSK364735 due to assay sensitivity, limited PK sampling window, and/or variable absorption. The less-than-expected accumulation following the q8h dosing is likely due to large PK variability over time.

Repeated-dose administration of GSK364735 showed time-independent PK at doses of 100 mg q12h, 200 mg q12h, and 400 q24h but not at doses of 50 mg q12h or 200 mg q8h. At the dose of 50 mg q12h, day 8 AUC_0- was 41% higher than day 1 AUC_0-. This difference between day 8 AUC_0- and day 1 AUC_0- may likely be due to underestimation of t_1/2 or variable absorption and day 1 AUC_0- at 50 mg (the lowest dose studied). Following q8h dosing, AUC_0- at steady state was lower than AUC_0- on day 1. This finding is likely due to large PK variability over time but not due to induction, as induction was not observed at q12h and q24h dosing.

The results of the single- and repeated-dose escalations showed that the systemic exposure of GSK364735 increased less than dose proportionally and appeared to reach a plateau at 100- to 200-mg doses. The reduced oral bioavailability of GSK364735 as dose increased was likely due to solubility-limited absorption, as GSK364735 has low water solubility. The large PK variability of GSK364735 is likely due to variability in absorption and potentially metabolism via multiple metabolic pathways. Due to reduced absorption at high dose and high PK variability from the first-time-in-humans tablet, a new bioenhanced tablet formulation is currently being evaluated.

Based on review of available clinical data for integrase inhibitors raltegravir and elvitegravir, it is anticipated that the antiviral activity of integrase inhibitors is likely associated with plasma C_min (2, 4). Despite solubility-limited absorption, GSK364735 exposure (C_min) following dose administration at doses greater than 50 mg q12h exceeded the PA IC₉₀ of GSK364735 (0.062 µg/ml). The results of this study warrant further investigation of this compound in HIV-infected subjects.

 
We acknowledge Richard Hazen and Rob Ferris for generating data on antiviral activity of GSK364735. We also thank Jim Bishop for his assistance in measuring GSK364735 concentrations on an expedited basis.

 
* Corresponding author. Mailing address: GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-7203. Fax: (919) 315-4529. E-mail: sherene.s.min{at}gsk.com

Published ahead of print on 8 October 2007.

Present address: Gilead Sciences, Inc., Foster City, CA.

Present address: Pharmasset, Inc., Princeton, NJ.

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Antimicrobial Agents and Chemotherapy, December 2007, p. 4284-4289, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00716-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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