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Systemic and Renal Pharmacokinetics of Adefovir and Tenofovir Upon Coadministration

From Gilead Sciences Inc, Foster City, California. Informed consent was obtained from all subjects. This study was performed in compliance with current good clinical practice and was conducted under the review of the MDS Pharma Services Institutional Review Board, whose operations are in compliance with Section 56 of Title 21 of the Code of Federal Regulations. Financial support for this study was provided by Gilead Sciences Inc. The results of this study were presented in part at the 11th Conference of Retrovirus and Opportunistic Infections (CROI) (February 8-11, 2004, San Francisco, California) and was presented at the 15th International AIDS Conference (July 11-16, 2004, Bangkok, Thailand).

Address for reprints: Srinivasan Ramanathan, PhD, Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate and adefovir dipivoxil alone and together were determined in 24 healthy subjects in an 8-day, open-label, fixed-sequence study. Subjects received oral doses of adefovir dipivoxil on days 1 and 8 and oral doses of tenofovir disoproxil fumarate on days 2 to 8. Pharmacokinetic sampling was performed on days 1, 7, and 8. The plasma pharmacokinetics of tenofovir and adefovir were unaltered upon coadministration. Furthermore, the renal clearances (CL_renal) of tenofovir and adefovir were unaffected by their coadministration. The plasma C_max values of tenofovir and adefovir were 33-fold and 340-fold lower than their K_m values for the human renal organic anion transporter. These results demonstrate that coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil does not result in substantial changes to their individual pharmacokinetic profiles.

Key Words: Tenofovir • adefovir • pharmacokinetics • drug interaction • hOAT1

Tenofovir disoproxil fumarate is an orally bioavailable prodrug of tenofovir, an acyclic nucleotide analog of adenosine monophosphate (AMP), with activity in vitro against HIV type 1 (HIV-1) and HIV-2⁶ that is widely used as a component of antiretroviral regimens for both treatment-naive and treatment-experienced patients based on its efficacy and safety profiles in several clinical trials. Tenofovir has been shown to be a potent inhibitor of wild-type and lamivudine-resistant HBV replication in vitro⁷ and tenofovir disoproxil fumarate has demonstrated anti-HBV activity in HIV/HBV-coinfected patients in short-term pilot studies.^8,9

Because of their indications for the treatment of HBV and HIV, respectively, it is conceivable that adefovir dipivoxil and tenofovir disoproxil fumarate could be concurrently used in HBV/HIV-coinfected patients. Tenofovir and adefovir are both extensively eliminated renally via glomerular filtration and active tubular secretion.^10-12 Cihlar et al^13,14 have identified that tenofovir and adefovir are prototypical substrates for the human organic anion transporter 1 (hOAT1) using the Chinese hamster ovary (CHO) cells in vitro model. In this system, tenofovir (K_m = 33.8 ± 3.4 µM, V_max = 110 ± 12 pmol/10⁶ cells/min) and adefovir (K_m = 23.8 ± 4.2 µM, V_max = 46.0 ± 4.4 pmol/10⁶ cells/min) displayed carrier-mediated and saturable uptake kinetics in CHO cells stably expressing this transporter.¹³

Therefore, because of their common transport pathway, understanding the pharmacokinetics following the coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil was necessary to provide insight into the potential of renally mediated drug-drug interactions of these agents.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Healthy male and nonpregnant, nonlactating female subjects between ages 18 and 59 (inclusive) who were 60 kg in weight and within 25% of their ideal weight based on their height and body frame were eligible to participate in this study. Prior to enrollment in the study, all subjects provided informed written consent. Subjects were also required to be free of clinically significant disease or any condition that could jeopardize subject safety or study validity, as determined through their medical history, physical examination, and results from clinical laboratory tests that were performed within 2 weeks prior to the baseline visit (day 0). They were required to have unimpaired renal function (calculated creatinine clearance [CL_cr, estimated using the Cockcroft-Gault equation] >80 mL/min), have serum creatinine 1.5 mg/dL, and display no evidence of HIV, HCV, or HBV infection. Use of medications, including over-the-counter medications or herbal products (exclusive of vitamins, acetaminophen, hormone replacement therapy, and/or oral contraceptives), was not allowed within 1 week of commencing study drug dosing. Female subjects were required to be either surgically sterile, at least 2 years postmenopausal, or using an acceptable method of birth control from screening through completion of 30 days following the last dose of the study drug. Hormonal contraceptives were permitted when used in conjunction with a barrier method. Sexually active male subjects were required to practice 2 forms of barrier contraception from screening through completion of 30 days following the last dose of the study drug. Subjects with a history of drug sensitivity/allergy and alcohol/chemical dependency, considered by the investigator to hinder compliance with study-related procedures, were considered ineligible for participation.

Study Design
This study was an 8-day, open-label, fixed-sequence, drug-drug interaction study with multiple doses of tenofovir disoproxil fumarate and a single dose of adefovir dipivoxil. The study was conducted by the clinical unit of MDS Pharma Services (Phoenix, Ariz) using a protocol approved by the MDS Pharma Services Institutional Review Board and entailed a screening visit, a pretreatment visit, an 8-day treatment period, and a follow-up visit. The study was powered to discriminate a 20% difference in the systemic pharmacokinetics (C_max or AUC) of either agent (ie, tenofovir, adefovir) with 84% power. All subjects received a single oral dose of tenofovir disoproxil fumarate (300-mg tablet) on days 2 to 8 and a single oral dose of adefovir dipivoxil (10-mg tablet) on days 1 and 8. Subjects were admitted to the clinic on the evenings of days 0 and 6 and discharged on the mornings of days 2 and 9, respectively. On days 2 to 5, subjects participated as outpatients. On the morning of the pharmacokinetic study visits, study drugs were administered immediately following consumption of a standardized, light breakfast (ingested by subjects within 30 minutes).

Pharmacokinetic Sampling
Serial blood and urine samples were collected predose and over a 24-hour period following dosing on days 1, 7, and 8 for determining concentrations and assessing pharmacokinetic parameters of tenofovir and adefovir. Blood collection following adefovir dipivoxil dosing on day 1, tenofovir disoproxil fumarate dosing on day 7, and tenofovir disoproxil fumarate and adefovir dipivoxil dosing on day 8 was performed at 0/predose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 10.0, 12.0, and 24 hours. Plasma samples (7 mL) for the analysis of tenofovir and adefovir were collected in lavender-top Vacutainer tubes containing EDTA on days 1 (adefovir), 7 (tenofovir), and 8 (adefovir and tenofovir) and stored at or below –20°C until analysis.

All urine produced over time intervals 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 hours postdosing on days 1, 7, and 8 was collected. Subjects drank 8 oz of water at the end of each collection interval to facilitate urine production. At the end of each interval, the exact start time, stop time, total urine volume, and pH were measured and recorded. The urine samples from each collection interval were mixed by carefully inverting the collection vessel prior to pipetting one 6-mL aliquot of urine into the appropriately labeled urine storage tube and stored frozen at –20°C until analysis.

Bioanalytical Procedures
A high-performance liquid chromatographic method using mass spectrometric detection (LC/MS/MS) for the determination of adefovir and tenofovir in human plasma was developed and validated at MDS Pharma Services (MDS PS, St Laurent, Quebec, Canada).

An aliquot of human plasma (EDTA) containing adefovir, tenofovir, ²H₄-adefovir (internal standard), and ²H₆-tenofovir (internal standard) was extracted by the solid-phase extraction procedure using weak anion exchange (PSA, 100 mg, 1 cc; Varian, Palo Alto, Calif). The extracted samples were analyzed by high-pressure liquid chromatography (HPLC) equipped with an AB/MDS Sciex API 3000 mass spectrometer. Specifically, 15 µL of eluant was injected onto a 50 x 2.1-mm, 3.5-µm Symmetry C18 analytical column (Waters Corporation, Milford, Mass) with a 6%:94% MeOH/25-mM ammonium acetate mobile phase at a flow rate of 0.2 mL/min over 4.5 minutes. Positive ions were monitored in the selected reaction monitoring (SRM) positive ion mode and monitoring of m/z transitions of 288.2 176.1 for tenofovir and 274.2 162.1 for adefovir. A weighted quadratic regression was used to determine the concentration of adefovir and tenofovir. The calibration curves for adefovir (concentration range of 1.0-200 ng/mL) and tenofovir (concentration range of 1.0-500 ng/mL) in human plasma were linear, with correlation coefficients of 0.9976 and 0.9997, respectively. The lower limits of quantitation for both adefovir and tenofovir were set at 1.0 ng/mL. The interbatch precision (percentage coefficient of variation [%CV]) of low, medium, and high quality control (QC) samples was within the range of 2.3% to 3.8% for adefovir and 1.9% to 5.4% for tenofovir.

Pharmacokinetic Analysis
The pharmacokinetic parameters of each species (tenofovir, adefovir) were assessed either by application of a nonlinear curve-fitting software package using noncompartmental methods or were calculated directly in SAS (Statistical version; SAS Institute, Cary, NC). Where WinNonlin was used for parameter calculation, the linear/log trapezoidal rule was used in conjunction with extravascular input model 200, with input values for dose, time of dose, drug concentration, and corresponding real-time values based on drug-dosing times. The following pharmacokinetic parameters were evaluated for both adefovir and tenofovir: AUC_0-t, C_max, t_max, K_el, t_1/2z, CL/F, and V_Z/F. The following additional pharmacokinetic parameters were calculated: C_last, t_last, AUC_0-, and AUC_exp for adefovir and C and AUC_0- for tenofovir. The following pharmacokinetic parameters were calculated from urine data for adefovir and tenofovir: interval-specific A_e, cumulative A_e, CL_r, and %Dose A_e. In addition, CL_r(partial) was calculated for each urinary collection interval, using the following time-matched partial AUCs in plasma (ie, AUC_0-1.25, AUC_1.25-3.25, etc).

Statistical Methods
Plasma concentrations and pharmacokinetic parameters were calculated using actual blood draw times and were summarized using descriptive statistics, including arithmetic mean, standard deviation, coefficient of variation, and geometric mean. Differences in pharmacokinetics were assessed by the Student t test, with a P value of <.05 considered to represent a statistical difference between treatments. To interpret the magnitude and facilitate clinical interpretation of differences in pharmacokinetics, the 90% confidence interval (CI) about the ratio of the geometric means for C_max and AUC between the test (drugs together) and the reference (adefovir dipivoxil or tenofovir disoproxil fumarate administered alone) was compared to "noeffect" bounds of 80% to 125%, a standard for defining pharmacokinetic equivalence.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Safety
Twenty-four subjects enrolled, and 22 subjects completed the study. Fifteen of 24 subjects (63%) experienced at least 1 treatment-emergent adverse event (AE), with 4 subjects (17%) following adefovir dipivoxil dose alone, 13 subjects (54%) following tenofovir disoproxil fumarate dose alone, and 2 subjects (9%) following the combination treatment. A total of 57 treatment-emergent AEs were reported, and all were considered mild in severity (toxicity grade 1). Some of the AEs experienced by 3 or more subjects were mild headache (n = 7), mild nausea (n = 6), mild loose stools (n = 4), mild flatulence (n = 3), and mild vomiting (n = 3). The investigator considered 7 of the 57 AEs related to adefovir dipivoxil alone, 40 AEs related to tenofovir disoproxil fumarate alone, and 3 AEs related to the adefovir dipivoxil/tenofovir disoproxil fumarate coadministration. Seven AEs were considered unrelated to either drug. Two subjects were discontinued from the study because of AEs of vomiting during the tenofovir disoproxil fumarate–alone regimen. No serious AEs were experienced by the subjects during the study.

Pharmacokinetics of Adefovir
All 24 subjects received and completed at least 1 period of treatment and were included in the pharmacokinetic analysis. The mean (± SE) plasma concentration-time profiles for adefovir following adefovir dipivoxil dosing alone and in combination with tenofovir disoproxil fumarate are presented in Figure 1. The mean (± SD) pharmacokinetic parameters for adefovir following the 2 treatments are provided in Table I. The plasma concentration-time profiles for adefovir with and without tenofovir disoproxil fumarate dosing were similar. Following the oral administration of 10-mg adefovir dipivoxil on days 1 and 8, the maximum plasma adefovir concentrations, C_max, were attained within 1 to 4 hours for both treatments, and plasma half-life values of adefovir were comparable between days 1 and 8. The mean difference in adefovir C_max between the test and reference treatments was –7% (P > .05), whereas those for AUC_0-t and AUC_0- were –12% and –11%, respectively (P < .01); the 90% confidence intervals for test/reference for all 3 parameters were contained within the bounds of 80% to 125% (Table I).

View larger version (12K): [in this window] [in a new window]   Figure 1. Mean (SE) plasma concentrations of adefovir following dosing alone as adefovir dipivoxil (ADV) and with multiple doses of tenofovir disoproxil fumarate (TDF).

Adefovir Urinary Recovery and Pharmacokinetics
Urine collected during the study on days 1 and 8 was analyzed for adefovir in each collection interval over a 24-hour period. The mean (± SD) adefovir urinary recovery (Ae) over the 24-hour period was 2.2 ± 0.5 mg on day 1 and 1.8 ± 0.3 mg on day 8, accounting for 39.5% ± 9.4% and 32.5% ± 6.2% of each dose eliminated as an unchanged drug, respectivel. The urinary recovery of adefovir was lower on day 8 compared to day 1 by 17.6% (P < .05) and was consistent with the plasma data in which the day 8 to day 1 AUC_0-t ratio was 89.4%. The mean (%CV) renal clearances of adefovir on days 1 and 8 were not different (P > .05), with values of 200.4 mL/min and 193.4 mL/min, respectively.

Pharmacokinetics of Tenofovir
The mean (± SE) plasma concentration-time profiles of tenofovir following multiple-dose administration of tenofovir disoproxil fumarate alone and in combination with a single dose of adefovir dipivoxil are presented in Figure 2. The mean (± SD) pharmacokinetic parameters for tenofovir following the 2 treatments are presented in Table II. Peak tenofovir concentrations for both treatments were reached within 1 to 4 hours. No pharmacokinetic parameter was affected (P > .05) by coadministration with adefovir dipivoxil, and their 90% confidence intervals for test/reference were all contained within the bounds of 80% to 125% (Table II).

View larger version (11K): [in this window] [in a new window]   Figure 2. Mean (SE) plasma concentration of tenofovir following dosing alone as tenofovir disoproxil fumarate (TDF) and with a single dose of adefovir dipivoxil (ADV).

Tenofovir Urinary Recovery and Pharmacokinetics
The mean total amount of tenofovir recovered at steady state was 34.3 mg on day 7 and 34.4 mg on day 8, which accounted for 25.3% and 25.3%, respectively, of the dose of tenofovir disoproxil fumarate administered. The mean renal clearance values were 220 and 229 mL/min on days 7 and 8, respectively. Overall, the tenofovir urinary pharmacokinetics was similar for tenofovir after administration of tenofovir disoproxil fumarate alone or with adefovir dipivoxil.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Understanding the potential for drug-drug interactions in HIV/HBV-coinfected subjects is of particular importance as liver disease may also directly or indirectly alter the pharmacokinetics of drugs. Tenofovir and adefovir, nucleotide analogs of adenosine monophosphate, exhibit overlapping virologic, pharmacologic, and pharmacokinetic properties. Both agents are eliminated unchanged by renal clearance, with active tubular secretion mediated by hOAT1, located in proximal renal tubular cells. This study was performed with multiple doses of tenofovir disoproxil fumarate and single doses of adefovir dipivoxil in a fixed-sequence design. This design provided the achievement of clinically representative circulating concentrations of tenofovir and adefovir at the level of the kidney tubules based on the known pharmacokinetic profiles of tenofovir (serum half-life 17 hours) and adefovir (7 hours).¹⁵

This study showed no substantial alterations in the plasma pharmacokinetics of either adefovir or tenofovir upon their coadministration. Small differences in adefovir systemic exposures, without differences in renal parameters, were observed.

In the present study, the mean C_max values of tenofovir on day 8 (dosed with adefovir dipivoxil) and day 7 (alone) were 332 and 333 ng/mL (1 µM), respectively. Similarly, the mean C_max values of adefovir on day 8 (dosed with tenofovir disoproxil fumarate) and day 1 (alone) were 18 and 19 ng/mL (69 nM), respectively. These concentrations of tenofovir and adefovir are approximately 33-fold and 340-fold, respectively, lower than their K_m values for the hOAT1 transporter, thereby indicating that there is a low potential for alterations in the renal clearance of tenofovir or adefovir upon coadministration with other hOAT substrates or inhibitors.^13,14,16,17 This observation may be the result of the high capacity of the hOAT1 transport system in vivo to remove organic acids relative to circulating concentrations of exogenous substrates. This premise is further supported by the results from drug-drug interaction studies that found no renally mediated interactions between adefovir dipivoxil with lamivudine, acetaminophen, or ibuprofen,¹⁸ agents that can interact with the transport of acyclic nucleotides by hOAT1 in vitro.

All treatment-emergent AEs in this study were of grade 1 toxicity, and no serious AEs were reported. This was expected given the duration of the study and the known safety and tolerability profile of these 2 drugs. Furthermore, no clinically relevant trends were noted regarding clinical laboratory, vital sign, and physical examination findings, indicating that both tenofovir disoproxil fumarate and adefovir dipivoxil were safe and well tolerated by the subjects.

In conclusion, the present study demonstrated that the coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil did not result in any pharmacokinetic changes that would be expected to have clinically significant effects, based on what is known at this time about their specific pharmacokinetic profiles, and, specifically, that the renal clearance of tenofovir and adefovir was unaltered. These data and the in vitro determinations of their affinity for and the capacity of the hOAT1 transport system indicate there is a low potential for renally mediated drug-drug interaction of tenofovir and adefovir with other substrates/inhibitors of hOAT1.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors would like to thank Dr Gilbert Deray for his review and insightful comments on this article.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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11. Cundy KC, Barditch-Crovo P, Walker RE, et al. Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 1995;39: 2401-2405.[Abstract]

12. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase I/II of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001;45: 2733-2739.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Kearney, B. P. Articles by Shah, J. Search for Related Content PubMed PubMed Citation Articles by Kearney, B. P. Articles by Shah, J. Social Bookmarking                   What's this?