Pharmacokinetics and safety of the lopinavir/ritonavir tablet 500/125 mg twice daily coadministered with efavirenz in healthy adult participants

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (C(max)), plasma concentration prior to morning dosing (C(trough)), and area under the plasma concentration-time curve over a dosing interval (AUC(12)) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.     

Pharmacokinetic interaction between darunavir and saquinavir in HIV-negative volunteers

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n=14, panel 1; n=12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.     

Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system.
• Co-administration of ketoconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong both therapeutic and adverse effects.
• Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary.

WHAT THIS PAPER ADDS

• The current study was conducted to determine the extent of interaction between the potent CYP3A inhibitor, ketoconazole, and the CYP 3A substrate, darunavir (given alone and with low-dose ritonavir).
• This information provides data on the pharmacokinetic boosting ability of ketoconazole and serves as important guidance to HIV-infected patients and their treating physicians with regard to appropriate (co-)administration of darunavir/ritonavir and ketoconazole.

AIMS

To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV–healthy volunteers.

Methods

Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed.

Results

Based on least square means ratios (90% confidence intervals),during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC_12h), maximum plasma concentration (C_max) and minimum plasma concentration (C_min) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC_12h, C_max and C_min increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC_12h, C_max and C_min increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone.

Conclusions

The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day⁻¹ is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.     

Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

AIMS: To evaluate the pharmacokinetic interaction between ritonavir and mefloquine. METHODS: Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies. Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose. Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose. Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2. RESULTS: Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins. Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics. Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%). Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98%. CONCLUSIONS: Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.     

Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study

BACKGROUND AND OBJECTIVES: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. METHODS: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. RESULTS: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. CONCLUSION: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.     

Ciprofloxacin disposition in elderly patients with LRTI being treated with sequential therapy (200 mg intravenously twice daily followed by 500 mg per os twice daily): comparative pharmacokinetics and the role of therapeutic drug monitoring

Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI). The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch i.v./os regimen of ciprofloxacin (200 mg i.v. bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI. The pharmacokinetic study was performed on a cohort of 17 elderly inpatients. Blood samples were collected in steady state conditions at appropriate intervals. Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package. The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower Cmax after i.v. administration and higher CL both after i.v. and oral administration). Cmax after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 +/- 0.9 mg/L vs 2.6 +/- 1.0 mg/L; p = 0.054). The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid i.v. administration (AUC(0-tau) 11.4 +/- 4.3 mg/L x h vs 5.5 +/- 1.8 mg/L x h). The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microorganisms (MIC < 0.1 mg/L). In fact, because the peak serum level to MIC ratio (Cmax/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC24h/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg i.v. bid regimen and a cost-effective treatment of LRTI. However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h i.v. and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-tau) or at least of Cmax should be performed to individualize therapy in this subpopulation.     

Steady-state pharmacokinetics and tolerability of indinavir-lopinavir/r combination therapy in antiretroviral-experienced patients

Six HIV-positive antiretroviral experienced patients initiating therapy with a regimen including lopinavir/ritonavir (400/100 mg twice per day) and indinavir (800 mg twice per day) underwent steady-state pharmacokinetic analysis. The AUC0-12 h of indinavir when combined with lopinavir/ritonavir was comparable with previously published data on indinavir/ritonavir 800/100 mg twice per day in HIV-infected individuals. However, lopinavir AUC0-12 h, Cmax, and C12 h were lower than previously reported in the absence of indinavir. The regimen was well tolerated, although 2 patients developed grade 3 hypertriglyceridemia. No patient discontinued the regimen because of indinavir-related urologic or retinoid-type adverse effects. Further study of the regimen with larger cohorts of patients is necessary.     

Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers

BACKGROUND AND OBJECTIVE: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIV-negative, healthy volunteers. METHODS: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout. RESULTS: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens. CONCLUSION: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.     

Clarithromycin bioequivalence study of two oral formulations in healthy human volunteers

OBJECTIVE: To assess the bioequivalence of two tablet formulations of clarithromycin (Clamicin 500 mg from Medley Indlistria Farmaceutica, Brazil, as the test formulation, and Biaxin 500 mg from Abbott Industries, USA, as the reference formulation). METHODS: A single 500 mg oral dose of each formulation was administrated in 24 healthy volunteers of both sexes (12 males and 12 females). The study was conducted open, randomized, two-period crossover design with a 7-day interval between doses. The plasma concentrations of clarithromycin were quantified by reversed phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM) method. 14-hydroxyclarithromycin concentration was estimated semiquantitatively as equivalent of clarithromycin/ml. The precision of the method was evaluated using calibration curves and plasma quality control samples. The pharmacokinetic parameters calculated for both compounds included: AUC(0 - 48h), AUC(0 - infinity), Cmax, Cmax/AUC(0 - 48h), Tmax, T1/2 and Ke. RESULTS: Standard curves of clarithromycin in plasma were linear in the range of 0.05 microg x ml(-1) to 10 microg x ml(-1) (r > 0.999). The limit of quantification was 5 ng/ml. Within- and between-run plasma quality control CV were 5.8% and 15.7%, respectively. Inaccuracy within- and between-runs were 14% and 17%, respectively. 90% CI for clarithromycin geometric mean AUC(0 - 48h), AUC(0 - infinity) and Cmax ratios (test/reference) were: 8.7% - 103.1%, 89.4% - 103.7% and 85.4% - 99.6%, respectively, and for hydroxyclarithomycin were 80.3% - 108.6%, 80.1% - 110.1% and 85.4% - 112.6%, respectively. CONCLUSION: The method described for the quantification of charithomycin and its main metabolite is accurate and sensitive. Clamicin was considered bio-equivalent to Biaxin based on the rate and extent of absorption. Since these were no significant differences in the bioequivalence determined using the pharmacokinetic parameters of either clarithromycin or 14-hydroxyclarithromycin, we suggest that future bioequivalence trials of this drug may be performed by quantifying clarithromycin only.     

Lack of interaction between enfuvirtide and ritonavir or ritonavir-boosted saquinavir in HIV-1-infected patients

Enfuvirtide (Fuzeon) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used to boost pharmacokinetic exposure to full-dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir-boosted saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both studies were single-center, open-label, one-sequence crossover clinical pharmacology studies in 12 HIV-1-infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of C(max) and AUC(12h) to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for C(max) (90% confidence interval [CI]: 109%-141%), 122% for AUC(12h) (90% CI: 108%-137%), and 114% for C(trough) (90% CI: 102%-128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for C(max) (90% CI: 94.3%-121%) and 114% for AUC(12h) (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for C(trough) (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir-ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low-dose ritonavir or saquinavir boosted with a low dose of ritonavir.     

Pharmacokinetics of extended-release and immediate-release formulations of galantamine at steady state in healthy volunteers

OBJECTIVE: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24-mg qd capsule (GAL-ER) with and without food and to evaluate the relative bioavailability of GAL-ER with the immediate-release 12-mg bid tablet (GAL-IR) at steady state. METHODS: This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL-ER 8 mg qd each morning and 7 days of GAL-ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL-ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL-ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL-IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography. RESULTS: The treatment ratios of area under the plasma concentration-time curve of GAL from time 0-24 h post-dosing (AUC24 h), peak plasma concentration (Cmax), and pre-dose plasma concentration (Cmin) for GAL-ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL-ER bioavailability. As anticipated, GAL-ER (fasting) had mean AUC24 h similar to GAL-IR (fasting), with lower Cmax (63 ng/mL vs 84 ng/mL) and longer time to reach Cmax (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC24 h and Cmin demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for Cmax was 75.7%, indicating a 24% lower Cmax for GAL-ER than for GAL-IR. In this study, GAL-ER was safe and well tolerated with or without food and was comparable to the GAL-IR formulation. CONCLUSION: Food had no effect on the GAL bioavailability of GAL-ER at steady state. GAL-ER was bioequivalent to GAL-IR with respect to AUC24 h and Cmin.     

The effect of different meal types on the pharmacokinetics of darunavir (TMC114)/ritonavir in HIV-negative healthy volunteers

This open-label, randomized, crossover study investigated the bioavailability, short-term safety, and tolerability of darunavir (TMC114) coadministered with low-dose ritonavir under fasted conditions and after different meal types in HIV-negative healthy volunteers. All volunteers received ritonavir 100 mg twice daily on days 1 to 5, with a single darunavir 400-mg tablet given on day 3 (darunavir/rtv). Pharmacokinetic parameters for darunavir and ritonavir were determined under fasted conditions and following a standard breakfast, a high-fat breakfast, a nutritional protein-rich drink, or a croissant with coffee. Administration of darunavir/rtv in a fasting state resulted in a decrease in darunavir C(max) and AUC(last) of approximately 30% compared with administration after a standard meal. No significant differences in darunavir plasma concentrations were observed between different fed states. Darunavir/rtv should therefore be administered with food, but exposure to darunavir is not affected by the type of meal.     

Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin

HIV-1 protease inhibitors often cause dyslipidemia, necessitating the use of lipid-lowering agents such as rosuvastatin. However, when given concomitantly, these therapeutic agents often exhibit adverse drug interactions. In this study (phase I open-label trial, n = 12 HIV-1 seronegative participants), the authors assessed the drug interactions between darunavir/ritonavir given in combination with rosuvastatin. Participants were randomized to receive rosuvastatin (10 mg/day) or darunavir/ritonavir (600/100 mg twice daily) alone for 7 days in a crossover design followed by combination therapy for 7 days with intervening 7-day washout periods. Intensive blood sampling for pharmacokinetics and fasting lipids was performed on days 7, 21, and 35. The geometric mean AUC(0-24 h) of rosuvastatin increased from 109 to 161 ng·h/mL (P < .005) and C(max) increased 6.7 to 16.3 ng/mL (P < .001) when coadministered with darunavir/ritonavir. In the presence of darunavir/ritonavir and rosuvastatin, total cholesterol and triglyceride levels increased by 10% (P = .007) and 56% (P = .011), whereas the high-density lipoprotein cholesterol levels decreased by 13% (P = .006) relative to rosuvastatin administration alone. There were no significant adverse events attributable to the coadministration of these drugs. Rosuvastatin levels increase in the presence of darunavir/ritonavir coadministration, whereas the lipid-lowering benefits are blunted. The clinical significance of these changes requires further investigation.     

Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.     

Influence of SLCO1B1 Polymorphisms on the Drug-Drug Interaction Between Darunavir/Ritonavir and Pravastatin

The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.     

Comparative bioavailability of clarithromycin formulations in healthy brazilian volunteers

OBJECTIVE: To compare the bioavailability of clarithromycin 500 mg tablets (Merck S.A Industrias Quimicas, Sao Paulo, SP, Brazil, used as test formulation) and Klaricid (Abbott Laboratórios do Brasil Ltda, Sao Paulo, SP, Brazil, used as reference formulation) in 24 healthy volunteers. MATERIAL AND METHODS: The study was conducted using an open, randomized, two-period crossover design with one-week interval between doses. Blood samples were collected at pre-dose, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours after the administration. AUC was calculated by the trapezoidal rule extrapolation method. Cmax and tmax were compiled from the plasmatic concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(0-inf), AUC(0-24 h), Cmax and untransformed tmax. RESULTS: Intraindividual coefficient of variation (CV%) values were 14.25% and 12.62%, respectively for Cmax and AUC(0-24 h). The geometric mean values (+/- SD) for AUC(0-24 h) (microg x h/ml), AUC(0-inf) (microg x h/ml), and Cmax (microg/ml) for test medication were 18.56 (+/- 6.87), 18.8 (+/- 5.70) and 2.45 (+/- 0.88); the obtained values for reference medication were 18.29 (+/- 5.39), 19.10 (+/- 7.21) and 2.5 (+/- 0.69). 90% Cl for clarithromycin geometric mean of AUC(0-24 h), AUC(0-inf) and Cmax ratios (test/reference) were: 93.6-105.9%, 93.8-106.2% and 89- 103.2%. CCONCLUSION The test medication was considered bioequivalent to the reference medication based on the rate and extent of absorption.     

Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir

A total of 71 HIV-negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate-fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCtau were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCtau were decreased by 48% to 62% with the upper bound of the 90% CI 相似文献   

Open-label steady-state pharmacokinetic drug interaction study on co-administered quetiapine fumarate and divalproex sodium in patients with schizophrenia, schizoaffective disorder, or bipolar disorder

OBJECTIVE: To determine whether there is a pharmacokinetic drug interaction between quetiapine fumarate and divalproex sodium. METHODS: The pharmacokinetics and short-term tolerability and safety of coadministered quetiapine and divalproex were examined in adults with schizophrenia/schizoaffective disorder (Cohort A) or bipolar disorder (Cohort B) in an open-label, parallel, 2-cohort drug-interaction study conducted at three centers in the United States. Cohort A was administered quetiapine (150 mg bid) prospectively for 13 days, with divalproex (500 mg bid) added on days 6-13. Cohort B was administered divalproex (500 mg bid) for 16 days, with quetiapine (150 mg bid) added on days 9-16. Quetiapine and valproic acid plasma concentration-time data over a 12-h steady-state dosing interval were used to determine C(max), T(max), C(min), area under the plasma concentration-time curve (AUC(tau)), and oral clearance (CL/F). RESULTS: In Cohort A (n = 18), addition of divalproex did increase the C(max) of quetiapine by 17% but did not change AUC(tau). In Cohort B (n = 15), addition of quetiapine decreased both total valproic acid C(max) and AUC(tau) by 11%. No differences were observed in adverse events (AEs) with either quetiapine or divalproex monotherapy or their combination. CONCLUSION: Combination therapy with quetiapine (150 mg bid) and divalproex (500 mg bid) resulted in small and statistically non-significant pharmacokinetic changes.     

Hydrosoluble fiber (Plantago ovata husk) and levodopa II: experimental study of the pharmacokinetic interaction in the presence of carbidopa.

Levodopa combined with carbidopa constitutes one of the most frequent medication in the treatment of Parkinson's disease. Plantago ovata husk (water-soluble fiber) improves levodopa absorption conditions, but when this drug is administered with carbidopa, fiber could reduce its effectiveness. The purpose of this study is to investigate whether the presence of P. ovata husk modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route with carbidopa (5 mg/kg). We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). When levodopa and carbidopa were administered with 100 mg/kg P. ovata husk, the value of AUC for levodopa diminishes 29.7% (sign, n=6, P<0.05) and Cmax 28.1% (sign, n=6, P<0.05) in relation to the values obtained when these drugs were administered without fiber. If the dose of fiber was 400 mg/kg, the decrease was smaller: 20.4% for AUC (no significant difference) and 24.6% for Cmax (sign, n=6, P<0.05), that may indicate an inhibitory action of AADC by the fiber or any of its partial hydrolysis products. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 210 min with 100 mg/kg and 150 min with 400 mg/kg. The administration of P. ovata husk with levodopa/carbidopa to patients with Parkinson disease could be beneficial and in particular in those patients who also suffer constipation due to an improvement of levodopa kinetic profile with higher final concentrations, a longer plasma half-life and lower Cmax.