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DRUG INTERACTIONS |
From Gilead Sciences, Inc, Durham, North Carolina.
Address for reprints: M. Robert Blum, PhD, Gilead Sciences, Inc, 4 University Place, 4611 University Drive, Durham, NC 27709; e-mail: robert.blum{at}gilead.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, Cmax, and Cmin) of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) in combination were essentially equivalent versus each drug alone, providing a pharmacokinetic rationale for combining these products in emtricitabine/tenofovir disoproxil fumarate fixed-dose tablets.
Key Words: Emtricitabine • tenofovir DF • pharmacokinetics • drug interaction • renal elimination
Despite the availability of a range of potent antiretroviral agents, some patients do not achieve adequate viral suppression even with combination therapies. The causes of virologic failure are complex, but one of the most important factors is incomplete adherence to the antiretroviral regimen.3
The development of fixed-dose combination antiretroviral products is 1 strategy to simplify regimens and improve adherence to therapy. The choice of 2 potent and well-tolerated once-daily NRTIs and/or NtRTIs as the backbone for the development of fixed dose combination would allow the flexibility of combining with other once-daily NNRTI(s) or PI(s). With these considerations, emtricitabine (FTC), an NRTI, and tenofovir disoproxil fumarate (tenofovir DF, TDF), an NtRTI, were considered ideal candidates for the development of a once-daily, fixed-dose combination product. Both are potent antiretroviral agents already approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection, with each drug administered once daily as a single pill.
Before combining emtricitabine and tenofovir DF in a single pill, both the pharmacodynamic and pharmacokinetic aspects of this combination needed to be considered. In vitro experiments had shown that emtricitabine in combination with tenofovir DF produced synergistic antiretroviral activity.4 In addition, tenofovir DF exhibits a unique and favorable resistance profile against HIV-1; in particular, it displays activity against viruses containing mutations that confer reduced sensitivity to nucleoside analogs5-7 and only rarely selects for virus mutations, with K65R substitution being the only identified mutation in vitro and in vivo.7-9 The only identified mutation that confers resistance to emtricitabine is the M184V mutation, which confers resistance to lamivudine, zalcitabine, and abacavir10-12 but retains sensitivity to tenofovir DF, other NRTIs, and NNRTIs.4,9,11 The nonoverlapping resistance profiles of emtricitabine and tenofovir DF provided further pharmacodynamic rationale for developing these 2 drugs in a fixed-dose combination product.
From a pharmacokinetic perspective, it was important to determine if emtricitabine and tenofovir DF, when administered in combination, would affect the plasma profiles of each other. Emtricitabine is rapidly and extensively absorbed following oral administration, and systemic emtricitabine is also primarily eliminated via renal excretion, with about 60% to 70% of an oral dose recovered in urine as unchanged drug.13,14 Following oral administration, tenofovir DF is rapidly absorbed and converted to the active form, tenofovir. Tenofovir is eliminated from the systemic circulation by renal excretion.7,15 Renal excretion of both emtricitabine and tenofovir is via a combination of glomerular filtration and active tubular secretion.7,13 Because both drugs undergo little or no metabolism, they are not expected to have any potential pharmacokinetic interactions at the hepatic enzymes level.7,13 However, based on the renal excretion profiles, there was a hypothetical possibility of a pharmacokinetic drug-drug interaction between emtricitabine and tenofovir at the site of tubular secretion in the kidneys when the drugs are administered concomitantly. Thus, a steady-state pharmacokinetic study was conducted, as described herein, to formally evaluate the potential for a pharmacokinetic interaction between emtricitabine and tenofovir (administered as tenofovir DF). The results of this study provided a pharmacokinetic rationale for the development of a once-daily fixed-dose combination of emtricitabine and tenofovir DF, which is now commercially available in the United States and European Union as fixed-dose tablets.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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75 mL/min at screening. Subjects had to be nonpregnant, nontobacco users (90 days prior to screening), with no illegal drug or alcohol abuse within the previous 12 months. Negative serum ß-HCG test results (for women of child-bearing potential) and negative urine drug/alcohol screen results were required prior to entry. In addition, eligible subjects were to have negative screening tests for HIV, hepatitis B virus, and hepatitis C virus in accordance with the established practices of the study center. This study was conducted at the phase I clinic of MDS Pharma Services in Lincoln, Nebraska, over the period of October to November 2002. Prior to study initiation, the study protocol and informed consent form were approved by the MDS Pharma Services Institutional Review Board, and written informed consent was obtained from each prospective subject prior to the screening examination. The study was planned to enroll 18 eligible subjects who were randomized to receive each of the 3 treatments (denoted treatments A, B, and C) over a 21-day treatment period. Treatment A was emtricitabine (200 mg) administered once daily (FTC) in the morning for 7 consecutive days, treatment B was tenofovir DF (300 mg) administered once daily (TDF) in the morning for 7 consecutive days, and treatment C was the combination of emtricitabine (200 mg) and tenofovir DF (300 mg) administered simultaneously once daily (FTC plus TDF) in the morning for 7 consecutive days. Each dose of emtricitabine was administered as 1 Emtriva® capsule, and each dose of tenofovir DF was administered as 1 Viread® tablet. There was no washout interval between treatments. Subjects received their first treatment on days 1 to 7, the second treatment on days 8 to 14, and the third treatment on days 15 to 21. The order in which each subject received the 3 treatments was determined by a randomization schedule based on a balanced Latin square design. The primary endpoint of this study was the plasma pharmacokinetic profiles of each drug when administered alone and in combination.
Study Procedures and Drug Administration
Eligible subjects were admitted to the clinic the evening before the first dose of the first treatment (day 0) for baseline clinical and laboratory evaluations. Serum pregnancy (as applicable) and urine drug/alcohol screens were performed at each admission for reverification of entry eligibility. The first dose of study drug(s) for each treatment was administered on days 1, 8, and 15, respectively, at the clinic under supervision, at approximately 8:00 AM. The next 3 doses of each treatment (days 2-4, 9-11, and 16-18) were self-administered outside of the clinic at approximately the same clock time each morning (close to 8:00 AM), with study participants recording the date and time of each self-administered dose of study drug(s) on diary cards. Subject compliance with the self-administered doses was assessed by pill count and review of completed diary cards at each clinic visit. The last 3 doses of each treatment were administered at the clinic (days 5-7, 12-14, and 19-21) at approximately 8:00 AM under supervision. Full-profile pharmacokinetics (over 24 hours postdose) of emtricitabine and/or tenofovir were assessed at steady state on days 7, 14, and 21 (after the last dose administration for each treatment). Subjects were confined at the clinic the evening before each full-profile PK assessment and until the first dose of the next treatment had been given. A follow-up evaluation was performed 7 to 10 days after administration of the last dose of study drug(s).
The first dose of each treatment (ie, on days 1, 8, and 15) and the last 3 doses of each treatment (ie, on days 5-7, days 12-14, and days 19-21, respectively) were taken with or within 30 minutes (after) consumption of a standard breakfast that was served and eaten under the supervision of the clinic staff. All doses were administered with 240 mL of water. For the doses self-administered outside the clinic, the subjects were asked to take the drug(s) within 30 minutes (before or after) of consumption of their normal breakfast. During the full-profile PK assessments (ie, on days 7, 14, and 21), subjects were required to fast for at least 8 hours until consumption of breakfast, and then no food was allowed for 4 hours and no water was allowed for 2 hours after dosing. While fasting, subjects were allowed water ad libitum until 2 hours prior to dosing. The study required that subjects refrain from taking all prescription medications (other than hormonal contraceptives) for at least 14 days or longer (for long half-life drugs) prior to the first dose administration on day 1 and until completion of the last PK assessment on day 22. Nonprescription medications were prohibited for 3 days prior to each PK assessment until completion of the PK assessment. In addition, subjects were required to refrain from alcohol-containing food or beverages at least 3 days prior to day 1 until completion of the last PK assessment on day 22. During each PK assessment while the subjects were confined at the study clinic, no food or beverages containing caffeine or other xanthines were permitted.
Clinical and Laboratory Monitoring
The safety and tolerability of emtricitabine and tenofovir DF administered alone and in combination was assessed on the basis of adverse event reports; physical examination, including measurement of vital signs; and the results of clinical laboratory tests. A complete physical examination (including medical history) along with vital signs and clinical laboratory tests (hematology, serum chemistry, and urinalysis) was performed at screening for evaluation of entry criteria. Baseline measurements of these safety parameters prior to dosing and/or requalification of entry criteria were obtained at each admission to the study clinic (ie, prior to dosing on days 1, 7, 14, and 21), at completion of the last PK assessment on day 22 as part of an exit evaluation, and at the follow-up evaluation 7 to 10 days after the last dose of study drug(s). In addition, serum pregnancy and urine drug/alcohol screens were performed at each clinic admission for reverification of entry eligibility. All treatment-emergent adverse events were closely monitored throughout the entire treatment phase of the study and at the follow-up evaluation. The onset, duration, severity, and potential relationship to study drug(s) of any adverse events were recorded.
Pharmacokinetic Blood Sampling
Blood samples (3 mL for each collection) were collected at predose (
5 minutes prior to dosing) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours postdose of the study drug(s) on days 7, 14, and 21 (ie, after the last dose for each treatment) for determination of plasma concentrations of emtricitabine and/or tenofovir. Blood samples were drawn by individual needle stick into Vacutainer blood collection tubes containing spray-dried dipotassium EDTA and kept at 4°C upon collection. Within 2 hours of blood collection, plasma was separated by centrifugation at 4°C and stored at –20°C or lower until analysis.
Bioanalytical Methods
Plasma concentrations of emtricitabine and tenofovir were determined simultaneously using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Briefly, plasma sample (0.1 mL) was deproteinated with 0.4 mL of methanol containing the internal standards (ie, lamivudine for emtricitabine analysis and adefovir for tenofovir analysis). A 5-µL aliquot of the methanolic extract was then injected directly onto a high-performance liquid chromatography (HPLC)/MS/MS system. Emtricitabine, tenofovir, and the internal standards were all resolved on a reversed-phase chromatographic system under isocratic condition, consisting of a ThermoHypersil Keystone Aquasil C18 column (100 x 2.1 mm, 3 µm) maintained at 40°C. Retention times for adefovir, tenofovir, lamivudine, and emtricitabine were 3.0, 3.5, 3.7, and 6.3 minutes, respectively, using a mobile phase of 0.1% formic acid in water/methanol (85/15, v/v) at a flow rate of 125 µL/min. The compounds were detected by MS/MS in the selected reaction monitoring mode using electrospray ionization with positive polarity. The resulting chromatograms were constructed using the following precursor ion 
product ion transition: that is, m/z 288 m/z 176 for tenofovir, m/z 274 m/z 162 for adefovir, m/z 248 m/z 130 for emtricitabine, and m/z 230 m/z 112 for lamivudine. Quantitation of emtricitabine or tenofovir was based on the peak area ratios (to the respective internal standard) using a linear least squares regression with 1/concentration2 weighting. The ranges of quantitation were 0.005 to 2 µg/mL for emtricitabine and 0.01 to 1 µg/mL for tenofovir, respectively. The assay was specific for the determination of emtricitabine and tenofovir using the respective internal standards without endogenous interferences. For emtricitabine analysis, the intra- and interday precisions were 2.4% to 7.4% and 4.1% to 13.9%, respectively, and the intra- and interday accuracy of the assay ranged from –2.0% to 1.5% and –9.8% to 3.8% of nominal concentrations, respectively. For tenofovir analysis, the intra- and interday precisions were 2.2% to 8.3% and 5.2% to 14.4%, respectively, and the intra- and interday accuracy of the assay ranged from –2.0% to 8.1% and –9.0% to 2.4% of the nominal concentration, respectively.
Pharmacokinetic Data Analysis
Plasma emtricitabine and tenofovir concentration versus time data (0-24 hours) at steady state following administration of each drug alone or in combination were analyzed by noncompartmental methods using WinNonlin Professional Version 3.3 (Pharsight Corporation, Mountain View, CA) to determine the pharmacokinetic parameter estimates that included Cmax (maximal or peak plasma concentration at steady state), tmax (time at which Cmax occurred), Cmin (minimal or trough plasma concentration at steady state), AUC (area under the plasma concentration-time curve over a steady-state dosing interval, ie, from time 0 to 24 hours in this study), t1/2 (apparent plasma half-life), and apparent total body clearance at steady state (CL/F). The actual blood sampling times relative to the dosing time were used for all PK analyses. Cmax, tmax, and Cmin were the directly observed values from the plasma-concentration time profiles. AUC was determined by the log-linear trapezoidal method. The t1/2 estimate was determined by 0.693/
z, where z is the apparent first-order elimination rate constant determined by the slope of the terminal log-linear portion of the plasma concentration versus time curve. CL/F was determined as Dose/AUC.
Statistical Analysis
The critical pharmacokinetic parameters of interest for the assessment of potential pharmacokinetic drug interactions between emtricitabine and tenofovir (administered as tenofovir DF) were AUC, Cmax, and Cmin. These 3 parameters after log-transformation were compared between treatments (single-drug alone vs the 2 drugs taken together) by analysis of variance (ANOVA) using a linear mixed effects model (SAS PROC MIXED, Version 8.1, SAS Institute, Inc, Cary, NC). Treatments A and C were compared for potential differences in emtricitabine pharmacokinetics, and treatments B and C were compared for potential differences in tenofovir pharmacokinetics. The statistical model included period and treatment as fixed effects and subject (nested within sequence) as a random effect, along with assessment of carryover effect. Because the carryover parameter was not statistically significant, it was removed from the final statistical model. From the results of ANOVA, the ratio of geometric least squares means (LSM) and 90% confidence interval (CI) for the ratio of the geometric LSM of the test regimen (the 2 drugs taken together) versus the reference regimen (each single drug taken alone) was calculated for each critical PK parameter, based on the 2 one-sided t test procedure. The study was powered to detect a 30% difference in steady-state pharmacokinetics, and each drug's pharmacokinetics were considered to be equivalent (ie, not significantly altered from a clinical perspective) if the 90% confidence interval about the ratio of the geometric least squares means fell within the range of 70% to 143% (0.7-1.43). A no-effect boundary of 70% to 143%, representing a maximum change of 30%, was selected, based on the generally acceptable criteria for PK drug-drug interactions and because the combination of tenofovir DF and lopinavir-ritonavir had previously been shown to be a safe and efficacious antiretroviral therapy regimen in HIV-infected patients,17,18 notwithstanding the slightly higher tenofovir exposures (+34% in terms of AUC) observed when tenofovir DF is coadministered with lopinavir-ritonavir.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The 17 subjects who had evaluable pharmacokinetic data took all doses of study drug(s) according to the protocol without major deviations that would have adversely affected the study outcome. Subjects were also compliant with the restrictions of prior and concomitant medications and other restricted substances as required by the study protocol.
Pharmacokinetic Evaluation
The mean (± SD) steady-state plasma emtricitabine concentration versus time profiles following administration of 200 mg emtricitabine alone and in combination with 300 mg tenofovir DF within 30 minutes of food consumption are presented in Figure 1. The 2 mean plasma concentration versus time curves follow one another closely. The mean peak emtricitabine concentration appeared to be slightly lower without a change in peak time when the 2 drugs were taken together (FTC plus TDF); emtricitabine concentrations prior to the peak time also appeared to be slightly lower, but concentrations after the peak time were slightly higher when the 2 drugs were taken together. The pharmacokinetic parameter estimates for emtricitabine when taken alone or in combination with tenofovir DF are summarized in Table I. The mean steady-state peak plasma emtricitabine concentration following administration of emtricitabine alone was 1.77 µg/mL and occurred at 3.0 hours postdose, as compared to 1.69 µg/mL, also occurring at 3.0 hours postdose, when emtricitabine was administered together with tenofovir DF. The mean steady-state trough (Cmin) plasma emtricitabine concentrations were 0.064 and 0.075 µg/mL, respectively, for emtricitabine alone and for emtricitabine taken with tenofovir DF, and the overall plasma exposure to emtricitabine at steady state (AUC) was 10.2 h·µg/mL when taken alone and 10.7 h·µg/mL when taken with tenofovir DF.
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The mean (± SD) steady-state plasma tenofovir concentration versus time profiles following administration of 300 mg tenofovir DF alone and in combination with 200 mg emtricitabine within 30 minutes of food consumption are presented in Figure 2. The 2 mean plasma concentration versus time curves for tenofovir are essentially superimposable. The pharmacokinetic parameter estimates for tenofovir when given alone and together with emtricitabine are summarized in Table II. The mean steady-state peak plasma tenofovir concentration was 0.279 µg/mL, occurring at 2.4 hours postdose when tenofovir DF was given alone, as compared to 0.288 µg/mL, occurring also at 2.4 hours postdose when given together with emtricitabine. The mean steady-state trough plasma tenofovir concentration (Cmin) was the same at 0.054 µg/mL, both with and without emtricitabine. The overall plasma exposure to tenofovir at steady state (AUC) was 2.84 h·µg/mL following administration of tenofovir DF alone and 2.80 h·µg/mL when given with emtricitabine.
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The results of the statistical analysis comparing the critical PK parameters of emtricitabine or tenofovir taken alone or in combination are presented in Table III. The geometric LSM ratios (FTC plus TDF taken together vs FTC taken alone) for emtricitabine AUC, Cmax, and Cmin were 1.07, 0.96, and 1.20, respectively; the corresponding 90% confidence intervals for the geometric LSM ratios were 100% to 114%, 87% to 106%, and 112% to 129%, respectively, which were also all within the 70% to 143% no-effect boundary for a conclusion of no clinically significant differences in emtricitabine pharmacokinetics between treatments. The geometric LSM ratios (FTC plus TDF taken together vs TDF taken alone) for tenofovir AUC, Cmax, and Cmin were 1.00, 1.03, and 1.02, respectively; the corresponding 90% confidence intervals for the geometric LSM ratios were 92% to 109%, 95% to 111%, and 92 to 113%, respectively, which were all within the predetermined no-effect boundary for a conclusion of no clinically significant differences in tenofovir pharmacokinetics between treatments. Other than the upper bound of the 90% confidence interval for emtricitabine Cmin, the 90% confidence intervals for the AUC, Cmax, and Cmin for both drugs were also within the 80% to 125% boundary used to determine strict bioequivalence between treatments.
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Safety Evaluation
Both emtricitabine and tenofovir DF were generally well tolerated when administered alone and together for periods of up to 7 days each. There were no serious adverse events reported during the study. One female subject was discontinued by the investigator after taking 2 doses of study drugs (emtricitabine plus tenofovir DF) due to treatment-emergent adverse events. This subject reported multiple emetic episodes that onset approximately 8.5 hours after administration of the first dose of the study drugs and continued after administration of the second dose. The emesis was assessed as moderate in severity and related to the study drugs. In total, 48 adverse events were reported by 9 of the 19 subjects enrolled in the study. Most events (40/48) were assessed as at least remotely related to study drug(s). All events were assessed as mild (34/48) or moderate (14/48) in severity; none was severe. The only drug-related adverse events reported in 2 subjects were headache (5/19), nausea (4/19), somnolence (3/19), anorexia (2/19), and vomiting (2/19). There were no clinically relevant trends in abnormal (out-of-normal range) laboratory values, and none of the abnormal findings in individual subjects was considered to be clinically significant. There were no clinically relevant or significant findings or changes in physical examination or vital signs measurements.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Even though emtricitabine and tenofovir are both extensively eliminated from the systemic circulation via renal excretion with tubular secretion as one of the mechanisms, there were no clinically significant pharmacokinetic interactions between the 2 drugs, suggesting that the renal tubular secretory capacity for both drugs is high.21 Alternatively, different transporters may be involved in the tubular secretion of each drug, or the affinity of each drug to the transporter(s) may be much higher than the respective plasma drug concentrations. Lack of pharmacokinetic drug-drug interactions between tenofovir and other NRTIs (eg, lamivudine and didanosine) at the site of renal tubular secretion has also been reported.22,23 Emtricitabine has also been reported to have no pharmacokinetic drug-drug interactions with other antiviral nucleosides (eg, stavudine, zidovudine, and famciclovir).24-26
Based on the initial pharmacodynamic and pharmacokinetic assessments, emtricitabine and tenofovir DF were considered attractive candidates for the development of a fixed-dose combination to provide a dual NRTI/NtRTI backbone regimen. The in vitro synergistic antiretroviral activity for the combination of emtricitabine and tenofovir, along with their favorable resistance profiles against HIV-1, provided a strong virological foundation for this fixed 2-drug combination. In addition, both drugs have demonstrated long intracellular half-lives for the active moiety (ie, 
39 hours for emtricitabine-5'-triphosphate20 and 60 hours for tenofovir diphosphate).27 The lack of pharmacokinetic drug-drug interactions between emtricitabine and tenofovir, as shown in this study, and the long intracellular half-lives for both drugs are desirable and together set a strong pharmacokinetic foundation for the fixed-dose combination of tenofovir DF and emtricitabine.
In this study, concomitant administration of emtricitabine (200 mg) with tenofovir DF (300 mg) once daily in healthy volunteers for 7 days was well tolerated without any clinically significant abnormalities or safety concerns. The safety profiles of the fixed-dose combination of emtricitabine and tenofovir DF have been established in the clinic since its commercial introduction in the United States and European Union.
In conclusion, tenofovir DF and emtricitabine as a fixed-dose combination will provide choices of simplified regimens—for example, complete once-daily regimens containing a dual NRTI/NtRTI backbone as recommended by current clinical practice guidelines (http://aidsinfo.nih.gov/guidelines), along with reduced pill count, which together present the most desirable features in a regimen to improve patient adherence to antiretroviral therapy and ultimately maximizing long-term therapeutic success.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Sources for financial support: Gilead Sciences, Inc.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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