Interaction Studies of Tipranavir-Ritonavir with Clarithromycin, Fluconazole, and Rifabutin in Healthy Volunteers

ABSTRACT Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (C max), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC, C max, and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC, C max, and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC, C max, and Cp12h of TPV/r and RFB with 25-O-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.

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Pharmacokinetic Interactions between the Hormonal Emergency Contraception, Levonorgestrel (Plan B), and Efavirenz

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2012/137192 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 45

Author(s):

Monica L. Carten ◽

Jennifer J. Kiser ◽

Awewura Kwara ◽

Samantha Mawhinney ◽

Susan Cu-Uvin

Keyword(s):

Geometric Mean ◽

Liver Function Tests ◽

Open Label ◽

Time Curve ◽

Geometric Means ◽

Concentration Time ◽

Plan B ◽

Effective Contraception ◽

Grade 3 ◽

Hiv Negative

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV).Design. Prospective, open-label, single-arm, equivalence study.Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters.T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed.Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities.Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

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Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00862-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 6252-6259 ◽

Cited By ~ 28

Author(s):

John S. Bradley ◽

Jon Armstrong ◽

Antonio Arrieta ◽

Raafat Bishai ◽

Shampa Das ◽

...

Keyword(s):

Single Dose ◽

Phase I ◽

Pediatric Patients ◽

Geometric Mean ◽

Open Label ◽

Serious Adverse Events ◽

Time Curve ◽

Age Cohorts ◽

Concentration Time ◽

Systemic Antibiotic Therapy

ABSTRACTThis study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0–∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

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Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01313-05 ◽

2006 ◽

Vol 50 (7) ◽

pp. 2309-2315 ◽

Cited By ~ 31

Author(s):

Xiao-Jian Zhou ◽

Barbara A. Fielman ◽

Deborah M. Lloyd ◽

George C. Chao ◽

Nathaniel A. Brown

Keyword(s):

Single Dose ◽

Steady State ◽

Plasma Concentration ◽

Healthy Subjects ◽

Adefovir Dipivoxil ◽

Geometric Mean ◽

Time Curve ◽

Concentration Time ◽

Plasma Pharmacokinetics ◽

Plasma Concentration Time Curve

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (C max) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose C max and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state C max and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

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Pharmacokinetics of Indinavir Combined with Low-Dose Ritonavir in Human Immunodeficiency Virus Type 1-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.5.1904-1907.2004 ◽

2004 ◽

Vol 48 (5) ◽

pp. 1904-1907 ◽

Cited By ~ 10

Author(s):

A. S. Bergshoeff ◽

P. L. A. Fraaij ◽

A. M. C. van Rossum ◽

G. Verweel ◽

L. H. Wynne ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Low Dose ◽

Geometric Mean ◽

Time Curve ◽

Minimum Concentration ◽

Concentration Time ◽

Immunodeficiency Virus

ABSTRACT So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m2 combined with 125 mg of ritonavir/m2 every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.

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Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the EASIER-ANRS 138 Trial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01827-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3613-3615 ◽

Cited By ~ 9

Author(s):

Lauriane Goldwirt ◽

Joséphine Braun ◽

Nathalie de Castro ◽

Isabelle Charreau ◽

Aurélie Barrail-Tran ◽

...

Keyword(s):

Clinical Trial ◽

Human Immunodeficiency Virus ◽

Steady State ◽

Geometric Mean ◽

Plasma Concentrations ◽

Time Curve ◽

Concentration Time ◽

Background Regimen ◽

Immunodeficiency Virus ◽

Plasma Concentration Time Curve

ABSTRACTWe compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (Ctrough), maximum concentration of drug observed in plasma (Cmax), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.

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Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317517712890 ◽

2017 ◽

Vol 32 (6) ◽

pp. 360-366

Author(s):

Dhiraj Abhyankar ◽

Ashish Shedage ◽

Milind Gole ◽

Preeti Raut

Keyword(s):

Single Dose ◽

Standard Deviation ◽

Geometric Mean ◽

Bioequivalence Study ◽

Open Label ◽

Time Curve ◽

Healthy Men ◽

Time Zero ◽

Concentration Time ◽

To Receive

Objective: To assess the bioequivalence of generic formulation of rivastigmine (test) and Exelon (reference). Methods: This randomized, open-label, 2-period, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 40 healthy men under fed condition. Participants were randomized to receive a single dose of Exelon or rivastigmine capsule. Results: A total of 31 participants completed the study. Area under the concentration–time curve from time zero to time t (AUC0- t) and area under the concentration–time curve from time zero to infinity (AUC0-∞) for Exelon (mean [standard deviation], h·ng/mL) were 126.40 (56.95) and 129.46 (59.94), respectively, while they were 122.73 (43.46) and 125.08 (45.39) for rivastigmine. Geometric mean ratios of rivastigmine/Exelon were 99.17% for AUC0- t, 98.81% for AUC0-∞, and 105% for maximum observed plasma concentration ( Cmax). The 90% confidence intervals (CIs) were 94.14% to 104.46%, 93.77% to 104.12%, and 93.08% to 118.44%, respectively. Both formulations were well tolerated. Conclusion: The generic and reference formulations were bioequivalent, as the 90% CIs for Cmax, AUC0- t, and AUC0-∞ were within the range of 80% to 125%.

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Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04171-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1219-1224 ◽

Cited By ~ 17

Author(s):

Helen Winter ◽

Erica Egizi ◽

Stephen Murray ◽

Ngozi Erondu ◽

Ann Ginsberg ◽

...

Keyword(s):

Single Dose ◽

Healthy Adult ◽

Geometric Mean ◽

Pharmacokinetic Interaction ◽

Time Curve ◽

Concentration Time ◽

Period 2 ◽

Repeated Doses ◽

Single Sequence ◽

Time Point

ABSTRACTThis study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0–t), and AUC extrapolated to infinity (AUC0–inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for theCmax, AUC0–t, and AUC0–infof bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. TheCmax, AUC0–t, and AUC0–infof M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.)

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Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00449-09 ◽

2009 ◽

Vol 53 (10) ◽

pp. 4385-4392 ◽

Cited By ~ 40

Author(s):

P. A. Pham ◽

C. J. L. la Porte ◽

L. S. Lee ◽

R. van Heeswijk ◽

J. P. Sabo ◽

...

Keyword(s):

Single Dose ◽

Steady State ◽

Adverse Events ◽

Confidence Interval ◽

Geometric Mean ◽

Drug Reactions ◽

Open Label ◽

Time Curve ◽

Concentration Time ◽

Gastrointestinal Intolerance

ABSTRACT To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (C max) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the C max of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

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Single-Dose and Steady-State Pharmacokinetics of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.1.124-129.2004 ◽

2004 ◽

Vol 48 (1) ◽

pp. 124-129 ◽

Cited By ~ 39

Author(s):

Rohan Hazra ◽

Frank M. Balis ◽

Antonella N. Tullio ◽

Ellen DeCarlo ◽

Carol J. Worrell ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Single Dose ◽

Steady State ◽

Antiretroviral Therapy ◽

Tenofovir Disoproxil Fumarate ◽

Geometric Mean ◽

Transcriptase Inhibitor ◽

Time Curve ◽

Immunodeficiency Virus ◽

Tenofovir Df

ABSTRACT Tenofovir disoproxil fumarate (DF) is a potent nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV)-infected adults. The single-dose and steady-state pharmacokinetics of tenofovir were evaluated following administration of tenofovir DF in treatment-experienced HIV-infected children requiring a change in antiretroviral therapy. Using increments of tenofovir DF 75-mg tablets, the target dose was 175 mg/m2; the median administered dose was 208 mg/m2. Single-dose pharmacokinetics were evaluated in 18 subjects, and the geometric mean area under the concentration-time curve from 0 h to ∞ (AUC0-∞) was 2,150 ng · h/ml and the geometric mean maximum concentration (C max) was 266 ng/ml. Subsequently, other antiretrovirals were added to each patient's regimen based upon treatment history and baseline viral resistance results. Steady-state pharmacokinetics were evaluated in 16 subjects at week 4. The steady-state, geometric mean AUC for the 24-h dosing interval was 2,920 ng · h/ml and was significantly higher than the AUC0-∞ after the first dose (P = 0.0004). The geometric mean C max at steady state was 302 ng/ml. Tenofovir DF was generally very well tolerated. Steady-state tenofovir exposures in children receiving tenofovir DF-containing combination antiretroviral therapy approached values seen in HIV-infected adults (AUC, ∼3,000 ng · h/ml; C max, ∼300 ng/ml) treated with tenofovir DF at 300 mg.

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Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00194-08 ◽

2008 ◽

Vol 52 (9) ◽

pp. 3035-3039 ◽

Cited By ~ 10

Author(s):

Robert DiCenzo ◽

Derick R. Peterson ◽

Kim Cruttenden ◽

Peter Mariuz ◽

Naser L. Rezk ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Valproic Acid ◽

Geometric Mean ◽

Plasma Concentrations ◽

Plasma Samples ◽

Time Curve ◽

Dosing Interval ◽

Adjuvant Therapies ◽

Concentration Time ◽

Immunodeficiency Virus

ABSTRACT Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [± standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24), the plasma concentration 24 h after the dose (C min), and the maximum concentration during the dosing interval (C max) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC0-24, C min, and C max with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.

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