HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) 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 (12) Citing Articles via Google Scholar Google Scholar Articles by Lin, C.-c. Articles by Peterson, J. Search for Related Content PubMed PubMed Citation Articles by Lin, C.-c. Articles by Peterson, J. Social Bookmarking                   What's this?

Pharmacokinetics of Pradefovir and PMEA in Healthy Volunteers After Oral Dosing of Pradefovir

From Research and Development, Valeant Pharmaceuticals International, Costa Mesa, California.

Address for reprints: Dr Chin-chung Lin, Valeant Pharmaceuticals International, 3300 Hyland Avenue, Costa Mesa, CA 92626.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The pharmacokinetics of pradefovir and adefovir, 9-(2-phosphonylmethoxyethyl) adenine (PMEA), was evaluated in healthy male volunteers after oral dosing of pradefovir (10, 30, or 60 mg). Pradefovir was absorbed rapidly. The maximum serum concentration, the area under the concentration-time curve between 0 and 96 hours after dosing (AUC_0-96), and the area under the plasma concentration versus time curve from time 0 to infinity (AUC_0-) of pradefovir and PMEA increased with the dose of pradefovir. The ratio of PMEA to pradefovir for AUC_0-96 and AUC_0- ranged from 1.4 to 1.8. Renal clearance of pradefovir (18-31 L/h) increased with the dose of pradefovir and was greater than glomerular filtration. The fraction of total body clearance due to renal clearance was low (0.045 to 0.083), suggesting that metabolic clearance played a significant role in the clearance of pradefovir in man. In addition, an evaluation of the food effect was conducted at the 30-mg dose. The results indicate that food intake has no effect on the extent of exposure of pradefovir and PMEA but may decrease the rate of systemic availability of PMEA.

Key Words: Pradefovir • adefovir dipivoxil • pharmacokinetics • hepatitis B • antiviral

Adefovir dipivoxil is an oral prodrug of PMEA. Clinical trials showed that it decreased serum HBV DNA and alanine amino transaminase levels at doses of 5, 10, 30, and 60 mg per day in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B.^9,10 However, there was dose-limiting kidney toxicity for adefovir dipivoxil. At the 30-mg dose, serum creatinine was significantly more elevated (0.3 to <0.5 mg/dL) from baseline than at the 10-mg dose.¹¹ Therefore, a suboptimal but safer dose of 10 mg was licensed.

Pradefovir (formerly known as remofovir or hepavir B) is a cyclodiester prodrug of PMEA. Rats given an oral dose (30 mg/kg) of [¹⁴C]pradefovir exhibited 15 times higher liver radioactivity levels and one third of kidney radioactivity levels than did rats given a 30-mg/kg oral dose of [¹⁴C]adefovir dipivoxil.¹² Because the liver is the target for HBV infection and the kidney is the site of toxicity, pradefovir is expected to have improved efficacy and lower toxicity compared with adefovir dipivoxil.

The aim of this study was to determine the pharmacokinetics of pradefovir and PMEA in healthy male volunteers after a single oral dose of 10, 30, and 60 mg of pradefovir. The effect of a high-fat meal on the pharmacokinetics of pradefovir and PMEA after oral dosing of pradefovir at 30 mg was also examined.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Drugs and Formulation
Pradefovir was formulated as 10-mg and 20-mg gelatin capsules. Placebo capsules, identical to pradefovir in appearance and formulation, except for the active ingredient, were formulated with microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and stearic acid.

Subjects
The study was conducted at the Guy's Drug Research Unit, Quintiles Ltd, London, United Kingdom. Healthy adult male volunteers ( 18 years of age) with a body mass index (BMI) between 18 and 30 kg/m² were enrolled in the study. Subject exclusion criteria included the following: (1) history of clinically significant metabolic, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, hepatic, renal, urologic, or psychiatric disorders; (2) history of hypersensitivity or allergies to pradefovir or to any drug compound, unless approved by the investigator; (3) history of stomach or intestinal surgery, except appendectomy or cholecystectomy; (4) history or presence of a clinically significant abnormal electrocardiogram (ECG); (5) history of alcoholism or drug abuse; (6) participation in a clinical trial and receiving an investigation drug within 3 months before the start of the study; (7) blood donation within 30 days before the start of the study; (8) poor peripheral venous access; (9) use of prescription or over-the-counter-drugs within 1 week before study entry; (10) refusal to abstain from the use of alcohol, caffeine, or grapefruit-containing products 1 week before the start of, and throughout, the study. All volunteers provided written informed consent to participate in the trial. The Guy's Hospital Research Ethics Committee provided formal approval for the study, which was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice. All subjects were admitted to the hospital on the day before receiving trial medication, and they remained in the unit under clinical supervision until at least 48 hours after dosing.

Study Design
Rising single dose study. This study was a double-blind, placebo-controlled, rising single-dose study. Eight subjects were assigned to group 1 (6 active treatment and 2 placebo), and 14 subjects were randomized to group 2 (12 active treatment and 2 placebo). Group 1 subjects were administered single oral doses of 10 mg and 60 mg pradefovir on 2 occasions, sequentially, with a washout period of approximately 3 weeks between doses. Group 2 subjects were administered single oral capsule doses of 30 mg pradefovir on 2 occasions, once in the fasted state and once after a meal (see below). Subjects fasted for at least 8 hours before dosing and continued to fast for approximately 4 hours after dosing. Group 1 subjects first received a 10-mg dose, and after confirmation of safety at the day 8 visit, Group 2 received a single dose of 30 mg pradefovir. Four days after dosing, Group 2 subjects were evaluated for safety and confirmation of tolerability, at which time group 1 subjects received a single 60-mg dose of pradefovir.

Food effect study. The effect of food (30-mg dose) was evaluated in group 2 subjects in a 2-period crossover design. Subjects received a single 30-mg dose of pradefovir or placebo after 8 hours of fasting. Fasting continued until 4 hours after dosing. After a 17-day washout period, subjects were given a second oral 30-mg dose approximately 1 hour after a standard 1000 kcal high-fat breakfast meal. The treatments (fed and fasting) were crossed over at the 17-day washout interval.

Blood samples (9.5 mL) were collected via an indwelling venous catheter into nonheparinized tubes before dosing and at 1, 2, 3, 4, 8, 12, 24, 48, 72, and 96 hours after dosing and allowed to clot at room temperature. Samples were centrifuged (2000 rpm for 15 minutes) within 15 minutes of collection, and the serum was stored at –70°C until analyzed. Urine samples from all subjects in the rising single-dose study were collected at 0 to 6 hours, 6 to 24 hours and 24 to 48 hours after dosing and stored at 4°C. At the end of the collection period, urine samples were immediately flash-frozen in dry ice and stored at –70°C until analyzed.

Safety was assessed by the incidence and severity of any clinically significant adverse events, and changes from baseline (screening) in physical examination findings, medical history, vital signs, ECG, and clinical laboratory tests. Laboratory analysis included hematology, clinical chemistry, and urinalysis variables and was performed before dosing, 24 hours after each dose, and at follow-up.

Bioanalytical Methods
Serum concentrations of pradefovir and pradefovir-derived PMEA were determined by a validated high-performance liquid chromatography/tandem-mass spectrometry (HPLC-MS/MS) method. Internal standard solutions (25 µL) of [¹³C]pradefovir and [¹³C]PMEA and 500 µL of 0.1 N hydrochloric acid (HCl) solutions were added to 500 µL serum sample and vortexed for 1 minute. The samples were partitioned onto MCX cartridges (conditioned by 1 mL methanol and 1 mL water), and the cartridges were rinsed with 1 mL 0.1 N HCl solution followed by 1 mL methanol. The analyte was eluted twice with 300 µL of 5% ammonium hydroxide/95% methanol:water (4:1) solutions each. The eluent was collected into a clean 16 x 100-mm tube and evaporated to dryness using a TurboVap evaporator (Caliper Life Sciences, Hopkinton, Mass; 5 psi N₂, 30°C). The sample was reconstituted in 150 µL of 3% DMHA/1.5% acetic acid in 10 mM ammonium acetate, and the extract was quantitatively analyzed for pradefovir and PMEA by HPLC-MS/MS. Urine samples were diluted with internal standards solution and 3% DMHA/1.5% acetic acid in 10 mM ammonium acetate before HPLC-MS/MS analysis.

An API 4000 mass spectrometer was used to validate the method and conduct the sample analysis. An XDB C-8 analytical column (4.6 mm x 150 mm, 5 µm) was used for the analysis. The analysis was performed using positive electrospray to monitor the ion transitions of 424 151 and 430 157 for pradefovir and [¹³C]pradefovir. For PMEA and [¹³C]PMEA, negative electrospray ionization was used to monitor the ion transitions of 272 134 and 277 139.

For serum analysis, the linear ranges were 0.0200 ng/mL to 2.56 ng/mL for pradefovir and 0.100 ng/mL to 12.8 ng/mL for PMEA. The limit of quantitation was 0.0200 ng/mL for pradefovir and 0.100 ng/mL for PMEA. The linear regression correlation coefficients (CV) for pradefovir and PMEA were 0.9971 and 0.9967, respectively. Interassay precision and accuracy as indicated by their respective precision (%CV) and relative error (%RE) from 3 concentrations were used for statistical evaluation. The %CV ranged from 5.7% to 11.9% for pradefovir and 4.9% to 12.6% for PMEA. The %RE ranged from –1.9% to 4.5% for pradefovir and –4.3% to –1.7% for PMEA.

For urine analysis, the calibration range was 10.0 ng/mL to 2560 ng/mL for both pradefovir and PMEA. The lower limit of quantitation was 10.0 ng/mL for both analytes. The linear regression CV for pradefovir and PMEA were better than or equal to 0.9943 and 0.9938, respectively. Interassay precision and accuracy as indicated by their respective %CV and %RE from 4 concentrations were used for statistical evaluation. The %CV ranged from 2.4% to 4.8% for pradefovir and 4.9% to 7.9% for PMEA. The %RE ranged from –7.2% to 12.0% for pradefovir and –7.3% to 4.4% for PMEA.

Pharmacokinetic Parameters
Pharmacokinetic parameters were estimated from serum concentration and urine excretion of pradefovir and PMEA using noncompartmental methods (WinNonlin Pro version 4.0, Pharsight Corp, Mountain View, Calif). The maximum serum concentration (C_max) and time of C_max (T_max) were observed values. The area under the concentration-time curve (AUC) to the last quantifiable sampling time, AUC_0-last, was computed using the linear trapezoidal rule. The area under the concentration versus time curve from time 0 to infinity, AUC_0-, was calculated as the sum of AUC_0-last,andthe quotient of the last measurable concentration, C_t, and the elimination rate constant (K). K was estimated as the negative slope of the regression of log concentration versus time. Half-life (T) was calculated by dividing 0.693 (ln/2) by K. The apparent total body clearance (CL/F) was calculated as the ratio of dose to AUC_0-.Fe is the cumulative amount of the drug excreted in the urine (Ae), expressed as a percentage of the dose. Renal clearance (CLr) is calculated as the ratio of Ae to AUC.

Statistical Analysis
All pharmacokinetic parameters were calculated using raw data. Values for T_max were displayed as nominal times. Because of the small number of volunteers who participated in the study, one may need to be cautious in the clinical significance of the findings.

In the food effect study, an analysis of variance was used to compare mean differences in sequence, period, and treatment. Variables were log-transformed before analysis. The 90% confidence interval (CI) for the difference between the fed state (test) and fasted state (reference) groups were obtained from the estimate statement of SAS PROC MIXED (SAS Institute, Cary, NC) procedure. An absence of a food effect was concluded if the 90% CI for the ratio of the geometric least square means for AUC from 0 to 96 hours after dosing (AUC_0-96) and C_max of fed and fasted treatments lay within 0.80 to 1.25. The C_max and AUC_t were dose adjusted; that is, the values were scaled to 1 mg. A logarithmic transformation was performed on the data before analysis, based on fundamental pharmacokinetic relationships and on empirical evidence.¹³

A mixed effects model, fitted by the method of residual maximum likelihood,¹⁴ was used to test for the effect of the dose, allowing for between subject and within-subject variability. The Satterthwaite formula^15,16 was used to calculate the denominator degrees of freedom. The significance level of the dose effect, for the dose-adjusted variable, provides evidence of nonproportionality.

View larger version (13K): [in this window] [in a new window]   Figure 1. Serum concentrations of pradefovir and PMEA in human after a single oral dose of pradefovir.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

Safety and Tolerance
The doses of pradefovir used in this study were considered generally well tolerated. There was no clear pattern of treatment-emergent adverse events. Of the 23 subjects who participated in the study, 10 reported treatment-emergent adverse events. The incidence of adverse events did not appear to be affected by the dose of pradefovir tested or by whether the subjects had been dosed in a fed or fasting state. The majority of adverse events were mild; 2 moderate adverse events were reported (diarrhea and vomiting) by one subject (30 mg pradefovir, fed period). All adverse events resolved without sequelae. The most common adverse event overall was upper respiratory tract infection, which was reported by 3 subjects, of whom 2 had received pradefovir and 1 had received placebo. No other adverse event was reported more than once. There was no obvious trend in any of the laboratory parameters, vital sings, physical examination results, or 12-lead ECG parameters after dosing of pradefovir or placebo.

Serum Pradefovir Pharmacokinetics
After single oral dosing of pradefovir, C_max of pradefovir was obtained 1.0 to 1.2 hours after administration, indicating rapid absorption of the drug. Thereafter, serum concentrations of pradefovir declined with time (Figure 1). The apparent T of pradefovir was about 10 hours (Table II). There was an increase in plasma pradefovir C_max, AUC_0-96, and AUC_0- with increasing doses of 10 mg to 60 mg of pradefovir. There was some evidence of statistical significance for nonproportionality of C_max (P = .050) but not for AUC_0-96. Apparent CL/F for pradefovir also appeared to be dose independent.

Serum PMEA Pharmacokinetics
After single oral dosing of pradefovir, serum concentrations of PMEA were obtained approximately 1.2 to 1.5 hours after administration, indicating rapid conversion of pradefovir to PMEA (Table II). Thereafter, serum concentrations of PMEA declined with time (Figure 1). The apparent T of PMEA ranged from 27 to 30 hours (Table II). There was an increase in PMEA C_max, AUC_0-96, and AUC_0- with increasing doses of 10 mg to 60 mg of pradefovir. The increases in C_max and AUC_0-96 were slightly higher than would be predicted from a linear proportional relationship with dose, but there was statistically significant evidence for nonproportionality for AUC_0-96 only (P = .020). The ratio of PMEA to pradefovir (P/R) for AUC_0-96 and AUC_0- ranged from 1.4 to 1.8, indicating ready conversion of pradefovir to PMEA. This ratio appeared to be independent of the pradefovir dose. The terminal T of PMEA was three times that of pradefovir.

Urinary Excretion of Pradefovir and PMEA
The Ae of unchanged pradefovir, as a percentage of dose, increased with dose. The CLr of pradefovir (18-31 L/h) was greater than glomerular filtration (125 mL/min or 7.5 L/h), suggesting involvement of tubular secretion of the drug in addition to glomerular filtration in the elimination of the drug into urine. CLr increased with a dose of pradefovir. The fe of CL/F due to CLr was low (ranging from 0.045 to 0.083), suggesting that metabolic clearance played a significant role in the clearance of pradefovir in man. This result is expected because pradefovir is a CYP3A4-activated prodrug of PMEA. The fe increased with a dose of pradefovir, suggesting possible saturation for the conversion of pradefovir to PMEA and other metabolites at higher doses.

The Ae of PMEA was probably incomplete during the 48 hours after dosing, as serum concentrations of PMEA were measurable in most subjects up to 96 hours after dosing, with the exception of those subjects administered 10 mg pradefovir. The Ae of PMEA increased from 0.246 mg after administration of 10 mg pradefovir to 2.66 mg after administration of 60 mg pradefovir. Therefore, a 6-fold increase in the dose of pradefovir resulted in a more than a 10-fold increase in the Ae of PMEA.

View larger version (12K): [in this window] [in a new window]   Figure 2. Serum concentrations of pradefovir and PMEA in human after a single oral dose of 30 mg pradefovir under fasted or fed state.

0-

0-

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The low oral bioavailability of PMEA^5-7 ultimately led to the design of a series of prodrugs intended to enhance its intestinal absorption. A bis(pivaloyloxymethyl) ester prodrug of the phosphonate, adefovir dipivoxil was selected for development based on its favorable properties.¹⁷ It has increased lipophilicity and greater intestinal permeability than does the PMEA in in vitro studies.^18,19 Adefovir dipivoxil at 10 mg was shown to be safe and efficacious and was approved by the Food and Drug Administration for the treatment of chronic hepatitis B. The 10-mg dose is suboptimal because at week 48, the log HBV DNA decline was 3.52 at a dose of 10 mg and 4.76 at a dose of 30 mg.²⁰ However, adefovir dipivoxil at 30 mg showed nephrotoxicity, with 42% of patients having serum creatinine increase to more than 0.3 mg/dL from baseline by week 48 of treatment.¹¹ After oral absorption, adefovir dipivoxil is rapidly and completely hydrolyzed to PMEA by plasma esterase.^5,21,22,23 Cihlar et al²³ reported that a human organic anion transporter, hOAT1, has high affinity to PMEA. It is proposed that hOAT1 may contribute to the accumulation of PMEA in renal proximal tubules and thus play an active role in the mechanism of nephrotoxicity associated with PMEA. This finding is consistent with the findings that [³H]PMEA, administered as an intravenous bolus injection, is mainly accumulated in the kidney.²⁴

Alternatively, Erion et al^25,26 reported a novel prodrug strategy for delivery of the nucleotide into the liver. The prodrug is efficiently and specifically activated through an oxidative reaction catalyzed by the liver cytochrome P450 isozyme CYP3A4.^27,28 In a whole body autoradiography study in rats after oral dosing (30 mg/kg) of [¹⁴C]adefovir dipivoxil or [¹⁴C]pradefovir, we have demonstrated that pradefovir produced 15 times higher radioactivity in the liver than adefovir dipivoxil but produced one third of the kidney radioactivity levels. After oral dosing (4 mg/kg) of [¹⁴C]adefovir dipivoxil or [¹⁴C]pradefovir to cynomolgus monkeys, pradefovir yielded 16 times higher total PMEA level (PMEA + PMEAp + PMEApp) in the liver but only two thirds of total PMEA levels in the kidney compared with adefovir dipivoxil.¹² These data clearly indicate that pradefovir has a good liver-targeting property and may have good safety profiles in animals.

The pharmacokinetics of intravenous and oral doses of 30 mg/kg [¹⁴C]pradefovir, a prodrug of PMEA, was studied in rats and in monkeys. Oral absorption and bioavailability, respectively, were 29.7% and 5.42% in rats, and 65.6% and 19.4% in monkeys. The elimination T for pradefovir was 0.7 hours in both rats and monkeys. The CL/F was 5.85 L/h/kg in rats and 2.60 L/h/kg in monkeys. Pradefovir was extensively converted to PMEA and other metabolites in both species after oral administration, with a faster rate of metabolism in rats than in monkeys. Urinary excretion of pradefovir accounted for 12.9% and 34.9% of the oral dose in rats and monkeys, respectively.

In the current study, T_max was 1.0 to 1.2 hours for pradefovir and 1.2 to 1.5 hours for PMEA after oral dosing of pradefovir, indicating rapid absorption of pradefovir and rapid conversion of pradefovir to PMEA. Increasing the dose of pradefovir administered resulted in increases in C_max, AUC_0-96, and AUC_0- for both pradefovir and PMEA. For pradefovir, there was some evidence by statistical significance testing for nonproportionality of C_max (P = .050) but not for AUC_0-96. For PMEA, the increases in C_max and AUC_0-96 were slightly higher than would be predicted from a linear relationship with dose, but there was statistically significant evidence for nonproportionality for AUC_0-96 only (P = .020).

The P/R for AUC_0-96 and AUC_0- ranged from 1.4 to 1.8, suggesting similar systemic exposure of pradefovir and PMEA in man at all doses evaluated. However, PMEA AUC obtained from 10 mg of pradefovir (37.7 ng·h/mL) was less than one fifth of that obtained from 10 mg of adefovir dipivoxil (210 ng·h/mL).¹¹ In a preliminary study, we have demonstrated that the ratio of kidney PMEA AUC to plasma PMEA AUC was about 2.8 in rats after oral dosing of either pradefovir or adefovir dipivoxil. Thus, the lower plasma PMEA levels would give lower kidney PMEA levels. These data suggest that pradefovir will have less potential for nephrotoxicity in man than will adefovir dipivoxil because oral dosing of pradefovir to man yielded lower plasma PMEA than did oral dosing of adefovir dipivoxil. The higher liver PMEA level should result in better clinical efficacy. However, we do not have any data on liver PMEA levels in man after oral dosing of pradefovir because liver biopsy samples will not be available until phase 3 clinical trials. A previous study¹² demonstrated that pradefovir has an excellent liver-targeting property and yielded high liver PMEA levels in rats and monkeys. We therefore predict that pradefovir will provide better clinical efficacy in man than will adefovir dipivoxil.

The terminal T of PMEA was 3 times that of pradefovir. The terminal T for both pradefovir and PMEA appeared to be independent of the dose. The amount of unchanged pradefovir Ae increased with the dose. The CLr of pradefovir (18-31 L/h) was greater than glomerular filtration (125 mL/min or 7.5 L/h), suggesting involvement of tubular secretion of the drug in addition to glomerular filtration in the elimination of the drug into the urine; CLr increased with a dose of pradefovir.

The effect of food on the pharmacokinetics of pradefovir and PMEA was evaluated in the current study. Based on log-transformed data, point estimates and CIs of C_max, AUC_0-96, and AUC_0- for fed versus fasted conditions after a single oral dose of 30 mg of pradefovir were determined. For both pradefovir and PMEA, 90% CIs were within the 80% to 125% guidelines for AUC_0-96 and AUC_0-. However, C_max for PMEA, CI was not contained in the 70% to 143% guidelines. These results indicate that food intake had no effect on the extent of exposure of pradefovir and PMEA. However, coadministration of food may significantly decrease the rate of systemic availability of PMEA.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 

1. Heijtink, RA, De Wilde GA, Krunining J, et al. Inhibitory effect of 9-2-phosphonylmethoxyethyladenine (PMEA) on human and duck hepatitis B virus infection. Antivir Res. 1993;21: 141-142.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

2. Heijtink RA, Kruining J, De Wilde GA, Balzarini J, De Clercq E, Schalm SW. Inhibitory effect of acyclic nucleoside phosphonates on human hepatitis B virus and duck hepatitis B virus infections in tissue culture. Antimicrob Agents Chemother. 1994;38: 2180-2182.[Abstract/Free Full Text]

3. Merta A, Vesely J, Votruba I, Rosenberg I, Holy A. Phosphorylation of acyclic nucleotide analogues HPMPA and PMEA in L1210 mouse leukemic cell extracts. Neoplasma. 1990;37: 111-120.[Web of Science][Medline] [Order article via Infotrieve]

4. Balzarini J, Hao Z, Herdewijn P, Johns DG, De Clercq E. Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl) adenine, a potent anti-human immunodeficiency virus compound. Proc Natl Acad Sci. 1991;88: 1499-1503.[Abstract/Free Full Text]

5. Cundy KC, Shaw JP, Lee W. Oral, subcutaneous and intramuscular bioavailability of the antiviral nucleotide analog 9-(2-phosphonylmethoxy-ethyl)adenine (PMEA) in cynomolgus monkeys. Antimcrob Agents Chemother. 1994;38: 365-368.[Abstract/Free Full Text]

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

7. Starrett JE, Mansuri MM, Martin JC, Tortolani DR, Bronson JJ. European Patent 481, 214, A1. April 1992.

8. Palu SS, Rassu M, Parolin C, Balzarini J, De Clercq E. Cellular uptake of phosphonylmethoxyalkylpurine derivatives. Antimicrob Agents Chemother. 1991;16: 115-119.

9. Heathcote E, Jeffers L, Wright T. Loss of serum HBV DNA and HbeAg and seroconversion following short-term (12 weeks) adefovir dipivoxil therapy in chronic hepatitis B: two placebo-controlled phase II studies. Hepatology. 1998;28(suppl): 317A.[CrossRef][Web of Science]

10. Heathcote EJ, Jeffers L, Perrilo R, et al. Serum HBV DNA suppression and seroconversion following long-term adefovir dipivoxil therapy in chronic hepatitis B patients. Hepatology. 2001;34: 316A.

11. Food and Drug Administration. Adefovir dipivoxil for the treatment of chronic hepatitis B. FDA Advisory Committee Brief Document. July 5, 2002. NDA 21-449.

12. Lin CC, Yeh LT, Vitarella D, Hong Z, Erion MD. Pradefovir mesylate: a prodrug of PMEA with improved liver-targeting and safety in rats and monkeys. Antiviral Chem Chemother. 2004;15: 307-316.[Medline] [Order article via Infotrieve]

13. Steinijans VW, Hauschke D. Update on the statistical analysis of bioequivalence studies. Int J Pharmacol Ther Toxicol. 1990;28: 105-110.

14. Giesbrecht FG, Burns JC. Two-stage analysis based on a mixed model: large sample asymptotic theory and small-sample simulation results. Biometrics. 1985;41: 477-486.[CrossRef]

15. Satterthwaite FE. Synthesis of variance. Psychometrika. 1941;6: 309-316.[CrossRef]

16. Satterthwaite FE. Biometrics Bulletin. 1946;2: 110-114.[CrossRef]

17. Starrett JE, Tortolani DR, Russel J. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonylmethoxyethyl)-adenine (PMEA). J Med Chem. 1994;37: 1857-1864.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Shaw JP, Cundy KC. Biological screens of PMEA prodrugs. Pharm Res. 1993;10(suppl): S294.[CrossRef]

19. Annaert P, Kinget R, Naesens L. Transport, uptake, and metabolism of the bis(pivaloyloxymethyl)-ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine in an in-vitro cell culture system of the intestinal mucosa (Caco-2). Pharm Res. 1970;14: 492-496.

20. Marcellin P, Chang T, Lim S, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348: 808-816.[Abstract/Free Full Text]

21. Naesens L, Balzarini J, Bisshofberger N. Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonyl-methoxyethyl)adenine. Antimicrob Agents Chemother. 1996;40: 22-28.[Abstract]

22. Barditch-Crovo P, Toole J, Hendrix CW, Cundy C, Ebeling D, Jaffe HS, Lietman PS. 1997. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bispivaloyloxymethyl)-phosphonylmethoxyethyl] adenine) in HIV-infected patients. J Infectious Disease. 1997;176: 406-413.

23. Cihlar T, Rosenberg I, Votruba I, Holy A. Transport of 9-(2-phosphonylmethoxyethyl) adenine across plasma membrane of HeLa S3 cells I protein mediated. Antimicrob Agents Chemother. 1995;39: 117-124.[Abstract]

24. Naesens L, Balzarini J, De Clercq E. Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxyethyl)adenine. Drug Met Dispos. 1992;20: 747-752.[Abstract]

25. Erion M, Reddy K, Boyer S, et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph9on)ate-based drugs to the liver. J Am Chem Soc. 2004;126: 5154-5163.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

26. Erion M, van Poelje P, MacKenna D, et al. Liver-targeting drug delivery using HepDirect prodrugs. J Pharmacol Exp Therap. 2005;312: 554-560.[Abstract/Free Full Text]

27. Hall SD, Thummel KE, Watkins PB, et al. Molecular and physical mechanisms of first-pass extraction. Drug Met Dispos. 1999;27: 161-166.[Abstract/Free Full Text]

28. De Kanter R, De Jager MH, Draaisma AL, et al. Drug-metabolizing activity of human and rat liver, lung, kidney and intestine slices. Xenobiotica. 2002;32: 349-362.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. M. Fujitaki, E. E. Cable, B. R. Ito, B.-H. Zhang, J. Hou, C. Yang, D. A. Bullough, J. L. Ferrero, P. D. van Poelje, D. L. Linemeyer, et al. Preclinical Pharmacokinetics of a HepDirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist Drug Metab. Dispos., November 1, 2008; 36(11): 2393 - 2403. [Abstract] [Full Text] [PDF]

				C.-c. Lin, C. Fang, S. Benetton, G.-f. Xu, and L.-T. Yeh Metabolic Activation of Pradefovir by CYP3A4 and Its Potential as an Inhibitor or Inducer. Antimicrob. Agents Chemother., September 1, 2006; 50(9): 2926 - 2931. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) 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 (12) Citing Articles via Google Scholar Google Scholar Articles by Lin, C.-c. Articles by Peterson, J. Search for Related Content PubMed PubMed Citation Articles by Lin, C.-c. Articles by Peterson, J. Social Bookmarking                   What's this?