Omeprazole absorption from a compounded transdermal formulation in healthy volunteers.

OBJECTIVE: To evaluate the plasma concentration versus time profile of omeprazole following the administration of a compounded transdermal gel formulation in healthy volunteers. DESIGN: Single-dose transdermal pharmacokinetic (PK) study including a comparison with historical data from an oral PK study. SETTING: Academic clinical research center. PARTICIPANTS: Eight healthy volunteers between 18 and 50 years of age. INTERVENTIONS: Omeprazole gel 40 mg (0.8 mL) was applied to the ventral surface of the forearm covering an area of 7 x 15 cm without an occlusive dressing. Blood samples were collected just before application and then at 1, 2, 3, 4, 6, and 8 hours. Plasma concentrations of omeprazole were determined using a validated liquid chromatography tandem mass spectrometry method. MAIN OUTCOME MEASURES: PK parameters (maximal plasma concentration [C(max)], the time of C(max), [T(max)], the area under the omeprazole concentration versus time curve from 0 to 8 hours, the elimination rate constant, and the half-life of the elimination phase) following transdermal administration, compared with historical controls who had received an oral omeprazole 40 mg dose during a previous study. RESULTS: Of the eight volunteers, five had undetectable plasma omeprazole concentrations throughout the 8-hour study, precluding a complete PK analysis. For the three volunteers with detectable plasma omeprazole concentrations, the values ranged from 0.204 to 0.552 ng/mL. Including values of 0 for the patients with undetectable levels, the mean (+/- SD) C(max) was 0.153 +/- 0.241 ng/mL, and the T(max) in patients with detectable levels occurred at approximately 6 hours. The plasma concentrations following transdermal administration were approximately 1,000-fold lower than those observed with oral dosing. CONCLUSION: Transdermal absorption from a single dose of the omeprazole gel formulation used in this study was poor. This transdermal gel formulation is clearly not bioequivalent to the oral capsule.

Cytochrome P450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction.

OBJECTIVE: Previous reports have supported the concept that messenger ribonucleic acid (mRNA) concentrations for cytochrome P450 (CYP) enzymes in peripheral blood mononuclear cells may be predictive of systemic enzyme activity. We investigated whether changes in mRNA expression for CYP1A2,CYP2C19, CYP2D6 and CYP3A4 in peripheral blood lymphocytes (PBLs) may serve as surrogate markers for changes in CYP enzyme activity following the administration of rifampin. METHODS: On day 1 and day 9 of the study, 12 healthy volunteers were administered caffeine 100 mg, debrisoquine 10 mg and omeprazole 40 mg orally, along with midazolam 0.025 mg/kg intravenously. Blood samples and urine were collected for 8 h after drug administration. The subjects took rifampin 300 mg (n = 6) or 600 mg (n = 6) daily on days 2-8. Total RNA was isolated from PBLs on day 1 and day 9, and mRNA expression for the CYP enzymes and hGAPDH were determined by means of quantitative, real-time, reverse-transcriptase polymerase chain reaction. CYP1A2 activity was estimated by calculating the plasma paraxanthine to caffeine AUC ratio (caffeine metabolic ratio; CMR), CYP2C19 activity by the 2-h omeprazole hydroxylation index (HI), CYP2D6 activity by the urinary debrisoquine recovery ratio (DBRR) and CYP3A4 activity by midazolam clearance. RESULTS: Median midazolam clearance (0.362 to 0.740 l/kg/h), omeprazole HI (0.752 to 0.214), CMR (0.365 to 0.450) and DBRR (0.406 to 0.479) all changed significantly following rifampin, consistent with the expected enzyme induction. CYP1A2,CYP2D6 and CYP3A4 mRNA content were measurable in all samples. CYP2C19 mRNA was inconsistently detectable. There were no significant correlations between changes in enzyme activity and mRNA expression by Spearman's rank order correlation. CONCLUSION: The results do not support the use of mRNA expression assays for CYP1A2, CYP2C19, CYP2D6 and CYP3A4 enzymes in PBLs as surrogates for quantifying changes in systemic enzyme activity in the setting of enzyme induction.

Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methadone.

STUDY OBJECTIVE: To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone. DESIGN: Phase I, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study. SETTING: Clinical research center. SUBJECTS: Fourteen volunteers receiving stable methadone maintenance therapy who were not infected with the human immunodeficiency virus. INTERVENTION: Tenofovir DF was added to the subjects' methadone regimens. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of total, R-, and S-methadone were evaluated at baseline and after 2 weeks of daily tenofovir DF coadministration with a light meal. Steady-state tenofovir DF pharmacokinetics were evaluated at day 15. Bioequivalence testing was conducted of total, R-, and S-methadone area under the serum or plasma concentration-time curve during the 24-hour dosing interval at steady state (AUCss) and maximum concentration in serum or plasma (Cmax). Subjects were evaluated for changes in methadone pharmacodynamics by the Short Opiate Withdrawal Scale (SOWS) and pupillary diameter measurements at frequent intervals. Coadministration with tenofovir DF did not affect the pharmacokinetics of methadone. Geometric mean R-methadone systemic exposures, AUCss and Cmax, differed by 5% or less when methadone was dosed with tenofovir DF. Similar results were observed for S-methadone and for total methadone. Both AUCss and Cmax met the strict criteria for bioequivalence between the two study periods for total, R-, and S-methadone, indicating a lack of drug interaction when tenofovir DF was coadministered with methadone. No significant changes in SOWS scores or pupillary diameter measurements occurred, and no notable clinical adverse events were reported. CONCLUSION: Tenofovir DF pharmacokinetics were comparable to previously reported values of tenofovir DF in HIV-infected patients. Coadministration of methadone with tenofovir DF did not alter the pharmacokinetics or pharmacodynamics of total, R-, or S-methadone. Tenofovir DF may be given as part of a once-daily antiretroviral regimen in patients receiving methadone maintenance therapy.

The effects of once-daily saquinavir/minidose ritonavir on the pharmacokinetics of methadone.

Twelve methadone-maintained HIV-negative subjects were given saquinavir/ritonavir (SQV/rtv) 1600 mg/100 mg once daily for 14 days. Pharmacokinetic evaluations of total and unbound methadone enantiomers (R and S) were conducted before and after SQV/rtv. SQV/rtv was well tolerated, with no ACTG Grade 3-4 adverse events, no evidence of sedation, and no changes in methadone dose. For R-methadone (active isomer), C(max), AUC(0-24 h), and C(min) were unchanged, but percent unbound 4 hours after dosing was reduced by 12%. For S-methadone, no differences in pharmacokinetic parameters of total drug were seen, but unbound concentrations were reduced by 15% and 21% at 4 and 24 hours after dosing, respectively. SQV trough concentrations exceeded the anticipated EC(50) (50 ng/mL) in 10/12 subjects, persisting for at least 6 hours after the final dose in 4/6 subjects. Once-daily SQV/rtv in methadone-maintained subjects is safe and not associated with any clinically significant interaction with methadone during 14 days of concomitant administration.

Effects of didanosine formulations on the pharmacokinetics of amprenavir.

STUDY OBJECTIVES: To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric-coated bead formulations) on amprenavir steady-state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation. DESIGN: Two-period, single-sequence, prospective, open-label drug interaction study with a 10-day washout interval. SETTING: Clinical research unit. SUBJECTS: Sixteen healthy volunteers without human immunodeficiency virus infection. INTERVENTION: Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12-hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric-coated bead formulation of didanosine. MEASUREMENTS AND MAIN RESULTS: Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high-performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration-time curve during one 12-hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric-coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12-hour concentration (C12) with concurrent administration of buffered or enteric-coated didanosine. CONCLUSION: Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric-coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric-coated bead formulation of didanosine in the fasting state.