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Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate on Coadministration With Lopinavir/Ritonavir

Kearney, Brian P PharmD; Mathias, Anita PhD; Mittan, Angelique BA; Sayre, John RN; Ebrahimi, Ramin MS; Cheng, Andrew K MD, PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1st, 2006 - Volume 43 - Issue 3 - p 278-283
doi: 10.1097/01.qai.0000243103.03265.2b
Clinical Science

Objective: Lopinavir/ritonavir (LPV/r) and tenofovir disoproxil fumarate (TDF) are frequently used antiretrovirals. A pharmacokinetic study in healthy volunteers was conducted to assess the potential for a drug interaction between these agents.

Methods: This was a 36-day, multiple-dose, drug-drug interaction study of TDF and lopinavir/ritonavir (LPV/r). Subjects received TDF alone for 7 days, followed by 14 days each of TDF plus LPV/r and LPV/r alone in a randomized manner. Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35. LPV/r and tenofovir plasma/serum concentrations were measured by high-performance liquid chromatography/mass spectometry (MS)/MS. Geometric mean ratios and 90% confidence intervals of pharmacokinetic parameters for tenofovir, LPV, and ritonavir (RTV) were estimated using analysis of variance and compared with the no-effect criterion for pharmacokinetic equivalence.

Results: Tenofovir measurements with an area under the concentration-time curve over the dosing interval, maximum concentration, and concentration at the end of the dosing interval (Cτ) were 32%, 15%, and 51% higher, respectively, when TDF was coadministered with LPV/r (n = 24). LPV and RTV pharmacokinetics, including Cτ, were unaffected by TDF (n = 24). Clinical estimates of renal function were unaffected by administration of TDF alone or with LPV/r.

Discussion: Coadministration of TDF with LPV/r resulted in increased tenofovir exposures at steady state, possibly through increased absorption. This increase is not believed to be clinically relevant based on the safety and efficacy of TDF plus LPV/r-containing regimens in HIV-infected patients in long-term controlled clinical trials.

From Gilead Sciences, Inc., Foster City, CA.

Received for publication March 29, 2006; accepted July 24, 2006.

Reprints: Brian P. Kearney, PharmD, 333 Lakeside Drive, Foster City, CA (e-mail:

Highly active antiretroviral therapy (HAART) regimens are defined as those containing at least 3 antiretroviral agents and combine a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI).1,2 Results from studies in treatment-naive patients have confirmed that NNRTI- and PI-based regimens can provide sustained virologic response;1-3 however, in drug-experienced patients, regimens that include PIs are necessary for complete viral suppression because of their high genetic barrier to resistance and the diversity of available agents within the class.4,5

In PI-based regimens, lopinavir/ritonavir (LPV/r) is a preferred agent because of demonstrated durable treatment responses among those who can tolerate adverse events related to ritonavir (RTV); virologic failure associated with the emergence of resistance is rare.2,6-9 In this combined-dose form, LPV is coformulated with a low dose of RTV, wherein the latter acts as a pharmacokinetic booster of LPV, increasing its bioavailability and increasing drug exposure. This and other RTV-boosted PI regimens generally allow for simpler dosing schedules with lower pill burden and less frequent administration, factors that are known to improve adherence, and thus outcomes of anti-HIV therapy.10,11 Moreover, boosting with RTV allows for high LPV trough concentrations, which have been shown to result in better treatment responses, even in patients whose HIV strains exhibit some degree of reduced susceptibility.

Several options for NRTIs are available, including a fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine, which is a recommended preferred backbone in treatment-naive and treatment-experienced patients.1,2 This NRTI combination offers the potential for the highest level of regimen simplicity-once-daily dosing-because of long plasma and intracellular half-lives for tenofovir diphosphate and emtricitabine triphosphate.12-14

Given the demonstrated tolerability, efficacy, and resistance profile of TDF, it is frequently included in LPV/r PI-based regimens.15,16 This necessitates attention to potential pharmacokinetic drug interactions on the coadministration of these drugs. Therefore, we conducted a drug-drug interaction pharmacokinetic study in healthy volunteers to assess the potential for interaction and provide, if necessary, a dosing recommendation for concomitant administration of these compounds. We examined the steady-state pharmacokinetics of LPV/r and tenofovir during multiple-dose administration of these agents relative to administration of LPV/r and TDF alone. As a secondary objective, we evaluated the safety of concomitant administration of these 2 agents.

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Study Population

Male or female subjects in good general health, weighing >60 kg, and between 19 and 59 years of age were eligible for this study. Subjects with a history of or current manifestations of clinically significant diseases or disorders or those who were receiving any prescription medication (30 days before study) or over-the-counter medication and herbal products (1 week before commencement of study), with the exception of vitamins, acetaminophen, and/or oral contraceptives, were excluded. Female subjects were required to use effective methods of contraception, including a barrier method. Moreover, 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 subjects were enrolled in the study. During the study period, medications such as chemotherapeutic agents, immunomodulatory agents, nephrotoxic drugs (eg, cidofovir, cyclosporine, tacrolimus), competitors of renal excretion (eg, probenecid, high-dose nonsteroidal anti-inflammatory drugs), investigational agents, or medications highly dependent on CYP3A or CYP2D6 for clearance (eg, midazolam, lovastatin, dihydroergotamine, ergotamine) were not allowed.

Written informed consent was obtained from each study participant. The protocol was approved by the MDS Pharma Services Institutional Review Board (Lincoln, NE) before study initiation. The study was carried out in accordance with the clinical research guidelines established by the basic principles defined in Volume 21 of the US Code of Federal Regulations (CFR), Part 312.20 and the principles enunciated in the latest version of the Declaration of Helsinki.

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Study Protocol

This study was a 36-day, open-label, multidose, crossover, 3-period, randomized drug-drug interaction study of TDF and LPV/r in healthy volunteers. Subjects enrolled received TDF (300 mg once daily) alone, followed by combination therapy with TDF (300 mg once daily) and LPV/r (400/100 mg [as 3 × 133.3 mg/33.3 mg] twice daily) or LPV/r (400/100 mg twice daily) alone when the sequence of LPV/r administration alone or with TDF was randomized (Fig. 1). All subjects received treatment with TDF alone on days 1 through 7 (period 1); this fixed portion of the study allowed for the study of 2 14-day back-to-back treatments with LPV/r (periods 2 and 3). This hybrid design was used to preclude starting, stopping, and reinitiating LPV/r treatments for some subjects in a fully randomized design that would require longer study duration, result in a higher number of dropouts, and necessitate additional washout periods for potential drug effects, including adverse events, and alterations in drug-metabolizing enzymes.



Subjects were randomized to sequence I or II and were given study drug(s) within 5 minutes of consuming a standard meal (approximately 400 kcal; 20% fat, 68% carbohydrate, and 12% protein). Subjects randomized to sequence I were administered LPV/r and TDF on days 8 through 21 (period 2), with the 2 agents simultaneously coadministered each morning and the second daily LPV/r dose administered each evening. On day 22, subjects discontinued TDF and continued LPV/r alone on days 22 through 35 (period 3).

Subjects randomized to sequence II were administered LPV/r alone from days 8 through 21 (period 2). On days 22 through 35 (period 3), subjects continued receiving LPV/r twice daily with concomitant TDF with the morning dose. Subjects documented timing and administration of study drugs with food with dosing diaries.

Pharmacokinetic assessments were performed over 24 hours on days 7, 21, and 35 after administration of the study drug(s). Subjects reported to the clinic on the evening before each assessment period. Subjects fasted overnight (approximately 12 hours) until a standard meal was served in the morning (30 minutes before dosing), and they received study drugs within 5 minutes of completion of their meal. Blood samples were collected at time 0, or before a dose (after consumption of the meal), and at 0.5, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0 hours after a dose before discharge from the clinic with the next study treatment, if applicable. Blood samples were centrifuged; plasma/serum was collected and frozen at −20°C until analysis.

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Safety Assessments

Clinical laboratory tests, physical examinations, and vital signs were evaluated at screening, before administration of first dose of study drug, and then at each subsequent pharmacokinetic visit. Finally, subjects were contacted by telephone 7 days after the last pharmacokinetic visit to assess adverse events. 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). Assessment of changes from baseline in creatinine clearance was calculated using the Cockcroft-Gault and abbreviated modification of diet in renal disease (MDRD) equations.17-19

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Bioanalytic Procedures

Tenofovir, LPV, and RTV concentration assays were conducted at MDS Pharma Services (Montreal, Quebec, Canada). The methodology used to quantify tenofovir in human serum has been described previously.20 The analytic method for the determination of LPV and RTV in human plasma was as follows. LPV and RTV were extracted from human plasma samples by a liquid-liquid extraction method and subjected to high-performance liquid chromatographic separation and quantitation on a Sciex API 3000 system (Applied Biosystems, Foster City, CA). LPV, RTV, and efavirenz (internal standard) were detected and quantified by mass spectrometry (MS) using selected reaction monitoring (SRM) MS/MS conditions with m/z transitions of 629 → 447, 722 → 296, and 316 → 244, for LPV, RTV, and efavirenz, respectively. The lower limit of quantitation (LLOQ) was 20 ng/mL for LPV and 5 ng/mL for RTV. Quality control samples (6 each at the LLOQ and at low, medium, and high concentrations) for LPV and RTV demonstrated an interbatch arithmetic mean (%CV) and bias percentage (%bias) from nominal values of <12% and <10%, respectively.

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Pharmacokinetic Analysis

The serum/plasma concentration-time data after oral administration of multiple doses of TDF and/or LPV/r were analyzed using the noncompartmental approach (WinNonlin, version 3.0; Pharsight, Mountain View, CA) to estimate the area under the concentration-time curve over the dosing interval (AUC(0-τ)), maximum concentration (Cmax), time to reach maximum concentration (Tmax), the concentration at the end of the dosing interval (Cτ), and plasma elimination half-life (T½).

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Statistical Methods

Based on the known pharmacokinetic profile of tenofovir, LPV, and RTV, the sample size of 27 subjects provided >80% power to discriminate 20% differences in exposures by pharmacokinetic equivalence testing using an analysis of variance (ANOVA) model appropriate for a 2-way crossover. From the ANOVA model, geometric means were estimated for AUC(0-τ), Cmax, and Cτ. Ninety percent confidence intervals (CIs) about the ratio of the geometric means (GMR) for each pharmacokinetic parameter between the test (TDF + LPV/r together) and the reference (TDF or LPV/r administered alone) were constructed and compared with “no-effect” bounds of 80% to 125% of a standard applied criterion for defining bioequivalence.21 Demographic baseline characteristics such as age, weight, height, gender, and race were summarized by descriptive statistics. Pharmacokinetic parameters were summarized by treatment using descriptive statistics. The T½ of tenofovir was assessed ad hoc to explore potential differences in drug elimination using the Wilcoxon signed-rank test (GraphPad Software; San Diego, CA).

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Subject Demographics

Twenty-seven subjects were enrolled in the study; all subjects satisfied all inclusion and exclusion criteria. The mean (standard deviation [SD]) age for the subjects was 34 (12) years, the average weight was 74.6 (7.5) kg, and the average height was 173 (6) cm. Sixteen subjects (59%) were men, and 11 (41%) were women (nonpregnant and nonlactating); 25 (93%) were white, 1 (4%) was African American, and 1 (4%) was European/Middle Eastern. Two subjects were discontinued by the Principal Investigator because of noncompliance with study requirements; 2 additional subjects withdrew consent because of adverse events, including ongoing diarrhea, while receiving LPV/r.

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TDF, LPV/r, and the combination were generally well tolerated. Of the 27 subjects dosed with at least 1 study treatment, 23 (85%) experienced at least 1 treatment-emergent adverse event: 12 subjects following TDF monotherapy, 19 subjects following LPV/r alone, and 18 subjects with TDF plus LPV/r combination therapy. Headache was the most common adverse event reported by subjects during TDF administration (22% subjects receiving TDF alone and 26% receiving TDF + LPV/r), and gastrointestinal events, including diarrhea, were the adverse events reported by the greatest number of subjects during administration of LPV/r (48% receiving LPV/r alone and 56% receiving LPV/r + TDF). No serious adverse events or deaths were experienced during this study. There were no changes in serum creatinine concentrations or calculated creatinine clearance by the Cockcroft-Gault or MDRD equations when patients were receiving TDF alone or in combination with LPV/r (Table 1).



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The pharmacokinetic analyses data set for tenofovir alone included 27 subjects, whereas the data set for LPV/r alone and their coadministration included 24 subjects. The mean (SD) serum concentration-time profiles for tenofovir after oral administration of TDF alone and in combination with LPV/r are presented in Figure 2. The mean (CV%) pharmacokinetic parameters estimated after the 2 treatments are summarized in Table 1. As seen in Figure 2, the tenofovir concentration-time profile is shifted upward throughout the dosing interval when TDF was coadministered with LPV/r. As a result, the pharmacokinetic parameters, AUC(0-τ), Cmax, and Cτ for TDF coadministered with LPV/r were approximately 32%, 15%, and 51% higher, respectively, as compared with those for TDF administered alone. The 90% CI of the GMR for AUC(0-τ) and Cτ fell outside the a priori range for pharmacokinetic equivalence. The Tmax and T½ for TDF administered alone or in combination with LPV/r were not different (P > 0.05; see Table 1).



The mean (SD) plasma concentration-time profiles for LPV and RTV after oral administration of LPV/r alone and in combination with TDF were superimposable (Fig. 3). Values for AUC(0-τ), Cmax, and Cτ and the 90% CI of their GMR for LPV and RTV were well within the bounds of pharmacokinetic equivalence after dosing alone or with TDF (Table 2). This indicates that the pharmacokinetics of LPV and RTV were unaltered by coadministration of TDF.





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This phase 1/2 study adds to the body of data regarding the drug-drug interaction potential between TDF and compounds cleared by metabolic biotransformation via cytochrome P450 isozymes.

Systemic exposure of tenofovir, AUC(0-τ), was increased (by 32%) when TDF was dosed with LPV/r. Given the different mechanisms of clearance of these compounds (renal vs. hepatic), an interaction at the biotransformation level is unlikely. Additionally, the elimination of tenofovir T½ was unchanged, suggesting that LPV/r did not alter tenofovir elimination. The human organic anion transporter (hOAT) and human multidrug-resistant protein 4 (MRP4) transporters are responsible for the influx and efflux, respectively, of tenofovir across renal proximal tubule cells.22 PIs have been shown not to alter hOAT- or MRP4-mediated tenofovir transport.23

Although tenofovir is metabolically stable and not a substrate for P-glycoprotein, the prodrug form of tenofovir (disoproxil) has been shown to have greater intestinal stability and cellular permeability in vitro with agents known to inhibit cellular esterase and P-glycoprotein activity.24,25 Recently, Ray et al26 have shown that a potential explanation for the increased tenofovir exposure with LPV/r may be via increased absorption in the gut. LPV/r and atazanavir have been shown to increase circulating tenofovir concentrations and are known to be transported by, and to potentially inhibit, P-glycoprotein.27-35

Of note, although this study was conducted before the availability of the new tablet formulation of LPV/r, the putative biologic mechanism on increasing the absorbed tenofovir dose indicates that the interaction between these 2 agents would likely occur with this new dosage form.

Tenofovir is eliminated as unchanged drug in the urine and is not a substrate, inducer, or inhibitor of CYP3A enzymes when evaluated in vitro and in a number of pharmacokinetic drug interaction studies in human beings.13 Moreover, to date, TDF has not been implicated in any clinically relevant drug-drug interactions with a number of agents that are hepatically metabolized, including efavirenz, indinavir, methadone, and oral contraceptives (ethinyl estradiol/norgestimate).15 On this basis, TDF would not be expected to exhibit a pharmacokinetic interaction with LPV or RTV, which undergo P450 metabolism via CYP3A.36-38 As expected, we observed that TDF did not alter the pharmacokinetics of LPV or RTV, as evidenced by the GMR and 90% CI for the GMR of AUC0-τ and Cmax falling well within the 80% to 125% bounds associated with pharmacokinetic equivalence. The LPV and RTV pharmacokinetics observed in this study were comparable to those observed in historical controls comprising healthy volunteers and HIV patients.38-40 Importantly, while not powered for this comparison a priori due to an expectation of large variability, lopinavir trough concentrations were equivalent when lopinavir/r was dosed with or without tenofovir DF. Considering that Cτ is the parameter responsible for the high barrier to the development of PI resistance, this finding is important to note.41,42 In addition, AUC0-τ, Cmax, and Cτ values for RTV, the pharmacokinetic booster, were demonstrated to be unaffected by TDF.

Higher tenofovir exposures did not result in any evidence of alterations in the safety profile for TDF in this short pharmacokinetic study. Specifically, there were no changes in serum creatinine or calculated creatinine clearance using the Cockcroft-Gault or MDRD equations.

This pharmacokinetic study confirms the lack of a clinically relevant pharmacokinetic drug-drug interaction between TDF and LPV/r that is consistent with the favorable safety and efficacy results from a 2-year study of once- versus twice-daily LPV/r coadministration with TDF plus emtricitabine.38,43,44

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drug interaction; lopinavir; ritonavir; tenofovir

© 2006 Lippincott Williams & Wilkins, Inc.