Mathias, Anita A PhD*; Hinkle, John PhD*; Menning, Mark PhD*; Hui, James PhD*; Kaul, Sanjeev PhD†; Kearney, Brian P PharmD*; for the Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen Development Team
Therapeutic strategies for treatment of HIV-1 infection have been markedly improved by the availability of potent combination highly active antiretroviral therapy (HAART), making it possible to suppress HIV-1 replication and reduce plasma HIV-1 RNA to undetectable levels.1-3 However, many patients exhibit incomplete viral suppression despite the availability of highly effective antiretroviral therapies.4-6 Successful long-term treatment of HIV/AIDS requires exceptionally high levels of adherence to therapy to prevent emergence of drug-resistant HIV variants with reduced susceptibility that leads to treatment failure and risk for disease progression.7,8 Incomplete adherence to the drug regimens is often a consequence of their complexity, frequent, and often discordant dosing intervals and side effects; therefore, strategies to simplify regimen adherence are desirable, particularly for first-line regimens, where adherence considerations are important determinants of treatment outcomes, including reduction of HIV-related morbidity and mortality.6,9 Availability of fixed-dose combinations such as the nucleoside/nucleotide combination of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) and other nucleoside combinations (eg, zidovudine/lamivudine [ZDV/3TC], abacavir sulfate/3TC, ZDV/3TC/abacavir sulfate) offer partially simplified treatment regimens by reducing pill burden and dosing frequency of the nucleoside backbone of HAART regimens.
Current clinical practice guidelines recommend the regimen of efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), plus FTC and TDF nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) as preferred agents for initial antiretroviral therapy for HIV-1 infection in adults.10-12 The combination of EFV, FTC, and TDF has demonstrated durable efficacy and safety in long-term controlled clinical trials.13-15 Long plasma half-lives of EFV, FTC and tenofovir (TFV) and longer intracellular half-lives of active anabolites of TFV and FTC make these agents amenable for once-daily dosing.16-18 Recently published data from Gallant et al15 have demonstrated that the combination of EFV, FTC, and TDF provides superior outcomes in terms of virologic suppression, CD4 cell response, and adverse events in treatment-naive patients compared with the previous gold-standard regimen of fixed-dose ZDV/3TC plus EFV.
The 25 years since the beginning of the HIV epidemic have seen the development of more than 20 antiretrovirals including 10 years of HAART; however, no simple single-tablet, once-daily, fixed-dose, standard-of-care regimen is available for patients. Therefore, with the goal of simplifying antiretroviral therapy, facilitating adherence, and optimizing durable treatment responses for patients, Gilead Sciences (Foster City, CA) and Bristol Myers Squibb (Princeton, NJ) have collaborated to develop a single, once-daily, fixed-dose, triple-combination tablet of EFV, FTC, and TDF. The current study was conducted to establish the bioequivalence of the fixed-dose, triple-combination, single-tablet regimen as compared with the commercialized individual dosage forms.
A total of 48 healthy male and female subjects (nonpregnant and nonlactating) between 18 and 45 years of age and with a measured body weight within ±15% of the protocol-specified range (as defined by 1999 Metropolitan Height and Weight Tables) were enrolled in the study. To rule out pregnancy, female subjects of childbearing potential had pregnancy tests (urine and plasma) at screening, before administration of study drug(s), and at several specified time points within the study. Laboratory values for all subjects had to be within the normal range, or if they were outside this range, deviations had to be assessed for clinical insignificance by the principal investigator and medical monitor. Subjects were excluded if they had a history or current manifestations of clinically significant diseases/disorders or were receiving any prescription medication (30 days before study) or over-the-counter medication and herbal product (2 weeks before commencement of study), with the exception of vitamins, acetaminophen, and/or hormonal contraceptives (oral, implant, patch, or injections). The prohibition toward use of medication(s) before commencement of study was extended to 60 days if the drug(s) exhibited an elimination half-life >10 days and to 30 days for drug therapy known to induce or inhibit hepatic drug metabolism. Additional restrictions included consumption of grapefruit juice or grapefruits 1 week before receiving study medication and until completion of the study. Subjects with a history of active alcohol or chemical dependency were excluded. The principal investigator reviewed medical histories and clinical laboratory evaluations and performed physical examinations before a subject's enrollment in the study.
Because EFV is assigned to US Food and Drug Administration (FDA) pregnancy category D, additional precautionary measures were implemented during the study to avoid/minimize the risk of developing pregnancies. Female participants of childbearing potential (ie, not surgically sterile or at least 2 years postmenopausal) were required to agree to use highly effective contraception methods while on study treatment and for 2 months after the last dose of study drugs. Highly effective methods included 2 separate forms of contraception, 1 of which was required to be an effective barrier contraceptive method. Female subjects using a hormonal contraceptive as a birth control method were required to have used the same method of contraception for at least 3 months before study dosing. Male subjects who were sexually active were required to use 2 forms of barrier contraception from screening through completion of the study and continuing for at least 30 days from the date of last dose of study drug and to refrain from sperm donation from day 1 through at least 30 days after the last dose of study drug.
Informed consent was obtained from each study participant. The protocol was approved by the MDS Pharma Services Institutional Review Board (Phoenix, AZ) before study initiation. The study was carried out in accordance with the clinical research guidelines established by the basic principles defined in the U.S. 21 CFR Part 312.20 and the principles enunciated in the latest version of the Declaration of Helsinki.
In accordance with FDA guidance for conducting bioavailability and bioequivalence studies for orally administered drug products, healthy subjects were investigated in this study.19 This allowed for removal of confounding effects of background antiretroviral and other therapies and avoidance of the potential for multiple short-term changes in treatment regimens of HIV-infected patients for the sole purpose of examining pharmacokinetic (PK) parameters.
This was a randomized, single-dose, open-label, 2-way, crossover study. The fixed-dose single-tablet regimen containing 600 mg of EFV, 200 mg of FTC, and 300 mg of TDF (EFV/FTC/TDF; test) was compared with concurrent administration of individual dosage forms of 600 mg of EFV, 200 mg of FTC, and 300 mg of TDF (EFV+FTC+TDF; reference treatment) to healthy adults under fasted conditions. All subjects received test and reference treatments. The duration of the study was 50 consecutive days and consisted of 2 periods: period 1 (day 1 to 28) and period 2 (day 29 to 50).
Subjects were randomized to 1 of 2 study treatment sequences (test→reference or reference→test). A single dose of study drug(s) was administered on days 1 and 29 under fasted conditions (8-hour fast). Mouth checks were performed after each dosing to ensure that subjects had ingested all study medication. Subjects continued fasting until after the 4-hour PK blood sampling time point.
Serial blood samples for PK assessments were collected over a 21-day (504-hour) period from days 1 to 22 and days 29 to 50 at the following time points: 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 240, 336, and 504 hours after oral administration of each treatment. The number, frequency, and timing of blood samples were based on the concentration-time profiles of the individual drugs to assess bioequivalence accurately based on maximum concentration (Cmax) and area under the concentration-time curve (AUC). An additional washout period of 1 week was introduced after the last blood sample draw in period 1 because of the long half-life of EFV.20 The blood samples were centrifuged, and plasma collected was frozen at −20°C until analysis.
The use of any prescription or over-the-counter medication, including those contraindicated in the individual drug(s) prescribing information, was prohibited during the study. Any concomitant medications that were required to be administered during the study needed review and approval from the sponsor.
Safety was evaluated by assessment of clinical laboratory tests at baseline and at various time points during the study; by periodic physical examinations, including vital signs; and by documentation of adverse events throughout the study. Subjects were also contacted by telephone 7 days after the last PK visit to inquire about any new adverse events. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 8.0. Adverse events and abnormal laboratory values were graded according to the Gilead Sciences Modified National Institute of Allergy and Infectious Diseases (NIAID) Common Toxicity Grading Scale (mild = 1, moderate = 2, severe = 3, and possibly life-threatening = 4).21
EFV, FTC, and TFV concentrations in human plasma were determined by a validated high-performance liquid chromatography/mass spectroscopy/mass spectroscopy (HPLC/MS/MS) assay. Briefly, the methodology was as follows: 100 μL of human plasma was deproteinized using methanol solution spiked with internal standard (IS). After extraction, EFV (IS: reduced EFV), FTC (IS: 3TC) and TFV (IS: adefovir) were resolved on reverse-phase chromatographic system under isocratic conditions, with a lower limit of quantitation of 5 ng/mL for EFV and FTC and 10 ng/mL for TFV. EFV and reduced EFV were detected in the selected reaction monitoring (SRM) mode using atmospheric pressure chemical ionization (APCI) with negative polarity and the following ion transitions: m/z 314→m/z 244 for EFV and m/z 286→m/z 216 for reduced EFV. FTC, TFV, and their ISs were detected in the SRM mode using electrospray ionization (ESI) with positive polarity and the following ion transitions: m/z 248→m/z 130 for FTC, m/z 288→m/z 176 for TFV, m/z 230→m/z 112 for 3TC, and m/z 274→m/z 162 for adefovir. Calibration curves for EFV and TFV were obtained using a linear regression algorithm of the peak area ratio of each analyte to its IS versus concentration. Calibration curves for FTC were obtained using a quadratic regression algorithm of the peak area ratio of FTC to 3TC versus concentration. The precision and accuracy in the assay validation were evaluated using 3 separate analytic runs, with each containing quality control (QC) samples (n = 4) in replicates of 5 for FTC and TFV and replicates of 6 for EFV. Inter- and intra-assay precision had a <13% coefficient of variation, and accuracy was within 16% of expected.
The PK analysis set for each analyte comprised all randomized subjects who received study drug and completed both PK sampling sessions. For analyses, all predose sample times of less than time 0 were converted to 0. Values less than the lower limit of quantitation in bioanalytic assays that occurred before the first quantifiable concentration were assigned a value of 0 to prevent overestimation of the initial AUC. Samples less than the lower limit of quantitation at all other time points were treated as missing data to avoid bias in the estimation of the terminal elimination rate constant. In accordance with FDA guidance for bioequivalence studies, subjects with a predose drug concentration in period 2 of >5% of Cmax or who experienced emesis at or before 2 times the median time to maximum concentration (Tmax) for the analyte were excluded from the PK analysis set.19
The plasma concentration-time data after oral administration of a single dose(s) of test and reference treatment were analyzed using a noncompartmental method (WinNonlin, version 5.0.1; Pharsight, Mountain View, CA) to estimate the area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last), area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf), Cmax, last quantifiable concentration (Clast), Tmax, time of Clast (Tlast), and terminal elimination half-life (T½).
For a 2-period crossover design, a total of 48 enrolled subjects (targeting 38 evaluable subjects for PK, with 19 subjects per sequence) were estimated to provide 90% power at the 5% significance level to reject the null hypothesis of lack of equivalence in favor of the alternative hypothesis of equivalence with regard to Cmax, AUC0-last, and AUCinf. Power was based on findings from previous studies (EFV, FTC, and TFV data on file, Gilead Sciences) and was determined by the within-subject SD of logarithmic transformed Cmax (0.211 for EFV, 0.198 for FTC, and 0.288 for TFV). Because equivalence on all primary endpoints was needed to declare overall bioequivalence between the test and the reference formulations, additionally, an estimate of overall “effective” power was determined by multiplying together the individual estimated power (for demonstrating equivalence) of each comparison. Effective power analyses estimated that 38 subjects (19 per sequence) would provide at least an 88% probability that bioequivalence was supported if the true geometric mean ratio (test/reference) was 1.00 for all endpoints and at least a 77% probability that bioequivalence would be supported if the true geometric mean ratio (test/reference) was 1.05 for all endpoints.
Demographic data and PK parameters were summarized by treatment using descriptive statistics. For each analyte (EFV, FTC, and TFV), the bioequivalence for primary PK parameters (Cmax, AUC0-last, and AUCinf) was analyzed using natural log-transformed values. These PK values were compared between the test and reference treatments by an analysis of variance (ANOVA) using SAS PROC MIXED (SAS Institute, Cary, NC) appropriate for a 2-treatment crossover design. The mixed-effects model included the following fixed effects: sequence, period, and treatment; it also included a random effect: subjects-within-sequence. In accordance with scientific standards and international guidelines for bioequivalence studies, formulation bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of the geometric least-squares means (test treatment/reference treatment) was within the bounds of 80% to 125% for the primary PK parameters (Cmax, AUC0-last, and AUCinf) for all analytes.19,22
Subject Demographics and Disposition
Forty-eight healthy subjects received at least a single administration of the test or reference treatment. Forty-five subjects received the test treatment, whereas 48 subjects received the reference treatment. The ethnic background of subjects was as follows: 90% Hispanic, 6% white, 2% American Indian, and 2% black. There was a greater proportion of female (73%) than male (27%) subjects. The mean (SD) age was 30 (7.1) years, mean weight (SD) at screening was 65.2 (7.15) kg, mean height (SD) was 163.3 (8.01) cm, and mean (SD) body mass index (BMI) was 24.5 (2.45) kg/m2 (24.3 kg/m2 for female subjects and 24.8 kg/m2 for male subjects). Forty-five subjects completed the study; 3 subjects were discontinued by the investigator for protocol violations (2 pregnancies and 1 positive drug test).
EFV, FTC, and TDF administered once daily in a fixed-dose combination tablet or as individual drugs given concurrently were generally well tolerated by the study subjects. Treatment-emergent adverse events were reported in 21 (46.7%) of 45 subjects after administration of the test treatment compared with 25 (52.1%) of 48 subjects receiving the reference treatment. Adverse events reported included central nervous system effects (primarily headache and dizziness) as the most frequent drug-related adverse events in 24.4% (test) to 29.2% (reference) of subjects. Gastrointestinal disorders (primarily nausea, abdominal pain, lower abdominal pain, and diarrhea) were the second most frequent treatment-emergent adverse events in 17.8% (test) to 16.7% (reference) of subjects. The adverse events were mild and transient and consistent with events commonly associated with EFV, FTC, and TDF.23-25
Two serious adverse events occurred during the study. Two female subjects had spontaneous abortions in the first trimester of pregnancy, and the subjects were discontinued from study during dosing period 1. Both subjects became pregnant on study after administration of the reference treatment on day 1 despite consensual agreement to all warnings and precautions relevant to pregnancy and explicit protocol requirements of contraception to avoid pregnancy. Details on these subjects were added to the antiretroviral registry to track the outcome of the pregnancy.
The PK analyses data set for EFV included 44 subjects, whereas the data set for FTC and TFV included 45 subjects. One subject had predose concentrations of EFV >5% of period 2 Cmax and was not included in the PK analysis criteria for EFV. Mean (SD) EFV, FTC, and TFV plasma concentration-time profiles are presented in Figure 1 (A-C, respectively). The derived plasma PK parameters for EFV, FTC, and TFV were similar after administration of the test or reference treatment throughout the monitoring period. Plasma PK parameters for EFV, FTC, and TFV after dosing of the test or reference treatment are summarized in Table 1, Table 2, and Table 3, respectively.
Statistical analyses of EFV, FTC, and TFV PK parameters after administration of the test or reference treatment are presented in Table 4. The ratios of the geometric means (%) of all primary PK metrics for EFV, FTC, and TFV were close to 1 (100%), and the corresponding 90% CIs around the ratio were contained within the bioequivalence bounds of 80% to 125%, indicating that the plasma PK parameters of EFV, FTC, and TFV after administration of the test treatment or reference treatment were bioequivalent.
The EFV/FTC/TDF coformulated single-tablet regimen and coadministered EFV+FTC+TDF did not differ with respect to the median Tmax or T1/2 value. As seen in Tables 1, 2, and 3, the amount of area under the curve that occurred after the last quantifiable sampling time point (%AUCexp) for any analytes was <17%, demonstrating adequate sampling and accurate estimation of the elimination phase and its rate constant. The mean [SD] apparent oral clearance (mL/h/kg) of EFV in these healthy subjects for the test (70.0 [21.7]) and reference (67.1 [23.6]) treatments was consistent with historical data (Bristol-Myers Squibb, data on file).
The results of this study demonstrate that the EFV/FTC/TDF fixed-dose, single-combination, single-tablet regimen is bioequivalent to the administration of commercially available EFV, FTC, and TDF, each of which is a preferred agent in the treatment guidelines for HIV infection in adults by the Department of Health and Human Services.10-12,26,27
All 3 agents of this regimen were developed to be administered once daily, and their long plasma (EFV ∼40 to 55 hours25) or intracellular (FTC ∼39 hours28 and TFV ∼>60 hours16) half-lives are complementary. In a large prospective trial with 517 treatment-naive patients, Gallant et al15 have demonstrated over 48 weeks that the combination of EFV, FTC, and TDF fulfilled the criteria for noninferiority to the well-established fixed-dose regimen of ZDV/3TC and EFV and proved superior in terms of virologic suppression, CD4 cell response, and adverse events resulting in discontinuation of the study drugs. The superior outcome in that study supports the use of EFV, FTC, and TDF as a standard-of-care regimen for treatment-naive patients starting therapy or for switching patients on this or other EFV-containing regimens. Offering this treatment in a single-tablet regimen provides the benefit of a simple regimen to facilitate adherence and lead to improved treatment outcomes.
Three previous formulations of the fixed-dose triple-combination tablet comprising an admixture of the 3 individual components had been developed using traditional dry and wet granulation methodologies; however, all 3 failed to demonstrate bioequivalence compared with the individual dosage forms. Factors such as high doses of active drugs, the low solubility/high permeability properties of EFV (Biopharmaceutics Classification System [BCS] class II), and chemical stability of TDF and FTC contributed to the difficulties in developing a coformulated single tablet. Formulation and process modifications were implemented, including bilayer tableting, to increase the dispersibility, absorption, and exposure of EFV in the fixed-dose combination tablet and to minimize potential physical and chemical interactions of EFV, FTC, and TDF. The proposed commercial formulation of the fixed-dose tablet that was assessed in this study is a bilayer film-coated tablet containing excipients such as croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. This design was proposed to increase the dispersibility of EFV and to enhance systemic exposure. This formulation was approved for commercialization in the United States by the FDA in July 2006 and is currently under regulatory review in the European Union and other countries.
Single doses of EFV, FTC, and TDF administered once daily in a fixed-dose triple-combination tablet or as individual drugs given concurrently were generally well tolerated by the study subjects. Adverse events reported included nervous system effects and gastrointestinal disorders; however, most events were mild and transient and consistent with events commonly associated with EFV, FTC, and TDF. In conclusion, the fixed-dose combination of EFV/FTC/TDF was bioequivalent to the individual dosage forms administered concurrently and is the first single-tablet, once-daily, complete antiretroviral regimen for the treatment of HIV-1 infection.
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