scholarly journals Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

2011 ◽  
Vol 55 (9) ◽  
pp. 4218-4223 ◽  
Author(s):  
Marta Boffito ◽  
Akil Jackson ◽  
Alieu Amara ◽  
David Back ◽  
Saye Khoo ◽  
...  
Keyword(s):  
Protein Binding ◽  
Half Life ◽  
Wild Type Virus ◽  
Pharmacokinetic Parameters ◽  
Type Virus ◽  
Wild Type ◽  
Minimum Effective Concentration ◽  
Once Daily ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACTThe object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC50] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC50for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.

scholarly journals Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

2002 ◽  
Vol 46 (3) ◽  
pp. 746-754 ◽  
Author(s):  
Mark Sale ◽  
Brian M. Sadler ◽  
Daniel S. Stein
Keyword(s):  
Protein Binding ◽  
Interaction Model ◽  
Pharmacokinetic Interaction ◽  
Wild Type Virus ◽  
Maximum Effect ◽  
Pharmacokinetic Parameters ◽  
Wild Type ◽  
Mixed Effect ◽  
Once Daily ◽  
Dosing Regimens

ABSTRACT Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear mixed-effect model). A two-compartment linear model with first-order absorption best fit the amprenavir data, while a one-compartment model was used to describe the ritonavir data. The inhibition of elimination of amprenavir by ritonavir was modeled with a maximum effect (E max) inhibition model and the observed ritonavir concentration. Monte Carlo simulation was then used to predict amprenavir concentrations for various combinations of amprenavir and ritonavir in twice-daily and once-daily dosing regimens. Simulated minimum amprenavir concentrations in plasma (C min) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) for clinical human immunodeficiency virus isolates with different susceptibilities to protease inhibitors (central tendency ratios). The model based on the first two studies predicted the results of the third study. Data from all three studies were then combined to refine the final model. The observed and simulated noncompartmental pharmacokinetic parameters agreed well. From this model, several candidate drug regimens were simulated. These simulations suggest that, in patients who have clinically failed a traditional amprenavir regimen, a regimen of 600 mg of amprenavir with 100 mg of ritonavir twice daily would result in C min-to-IC50 ratios similar to that of 1,200 mg of amprenavir twice daily alone for wild-type viruses. In addition, once-daily regimens that result in C mins above the protein binding-corrected IC50s for wild-type virus are clearly feasible.

scholarly journals Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

2010 ◽  
Vol 54 (7) ◽  
pp. 2775-2780 ◽  
Author(s):  
Gaik H. Soon ◽  
Ping Shen ◽  
Eu-Leong Yong ◽  
Paul Pham ◽  
Charles Flexner ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Half Life ◽  
Geometric Mean ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Time Curve ◽  
Once Daily ◽  
Drug Concentrations ◽  
Trough Concentrations

ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

Effect of the Addition of Ciprofloxacin on Theophylline Pharmacokinetics in Subjects Inhibited by Cimetidine

1992 ◽  
Vol 26 (1) ◽  
pp. 11-13 ◽  
Author(s):  
Robin L. Davis ◽  
Ronald W. Quenzer ◽  
H. William Kelly ◽  
J. Robert Powell
Keyword(s):  
Half Life ◽  
Repeated Measures ◽  
Enzyme Inhibitors ◽  
Enzyme Inhibitor ◽  
Combined Treatment ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Microsomal Enzyme ◽  
Elimination Half Life ◽  
Elimination Half

OBJECTIVE: Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, little data exist on the effects of combinations of inhibiting agents. The purpose of this study was to investigate the effect of the addition of a second hepatic oxidative enzyme inhibitor on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor. DESIGN: In a randomized crossover sequence, subjects received theophylline 5 mg/kg on day 6 of therapy with cimetidine 2400 mg/d, ciprofloxacin 1 g/d, both drugs, or while drug-free. SETTING: National Institutes of Health-funded General Clinical Research Center. PARTICIPANTS: Eight normal volunteers (6 men, 2 women; mean age 25.2 y). OUTCOME MEASURES: Theophylline pharmacokinetic parameters after each treatment were determined by model independent pharmacokinetic analysis. Statistical analysis of the data for differences between treatments was assessed by ANOVA for repeated measures. RESEARCH: When administered alone, ciprofloxacin and cimetidine caused a significant increase in theophylline elimination half-life and a decrease in clearance. Theophylline elimination half-life was significantly longer during combined therapy compared with either drug alone. Theophylline clearance was lower during combined treatment, although this relationship did not reach statistical significance. CONCLUSIONS: The addition of a second enzyme inhibitor in subjects receiving maximally inhibiting doses of cimetidine can produce a further decrease in the hepatic metabolism of drugs that are metabolized by the cytochrome P-450 microsomal enzyme system. As cimetidine and ciprofloxacin are frequently used together for a variety of common clinical indications, clinicians should be aware of this drug interaction and should consider that a similar effect may occur when other enzyme inhibitors are used concomitantly.

scholarly journals Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report

2021 ◽  
Vol 8 ◽  
Author(s):  
Joe S. Smith ◽  
Jonathan P. Mochel ◽  
Windy M. Soto-Gonzalez ◽  
Rebecca R. Rahn ◽  
Bryanna N. Fayne ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Half Life ◽  
Plasma Clearance ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Study Objective ◽  
Elimination Half Life ◽  
Elimination Half

Background: Ruminant species are at risk of developing abomasal ulceration, but there is a lack of pharmacokinetic data for anti-ulcer therapies, such as the proton pump inhibitor pantoprazole, in goats.Objective: The primary study objective was to estimate the plasma pharmacokinetic parameters for pantoprazole in adult goats after intravenous administration. A secondary objective was to describe the pharmacokinetic parameters for the metabolite, pantoprazole sulfone, in goats.Methods: Pantoprazole was administered intravenously to six adult goats at a dose of 1 mg/kg. Plasma samples were collected over 36h and analyzed via reverse phase high performance liquid chromatography for determination of pantoprazole and pantoprazole sulfone concentrations. Pharmacokinetic parameters were determined by non-compartmental analysis.Results: Plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 0.345 mL/kg/min, 0.7 h, and 0.9 L/kg, respectively following IV administration. The maximum concentration, elimination half-life and area under the curve of pantoprazole sulfone were estimated at 0.1 μg/mL, 0.8 h, and 0.2 hr*μg/mL, respectively. The global extraction ratio was estimated 0.00795 ± 0.00138. All animals had normal physical examinations after conclusion of the study.Conclusion: The reported plasma clearance for pantoprazole is lower than reported for foals, calves, and alpacas. The elimination half-life appears to be &lt; that reported for foals and calves. Future pharmacodynamic studies are necessary for determination of the efficacy of pantoprazole on acid suppression in goats.

scholarly journals Pharmacokinetics of Phenytoin: Reminders and Discoveries

2009 ◽  
Vol 9 (4) ◽  
pp. 102-104 ◽  
Author(s):  
Donna C. Bergen
Keyword(s):  
Elderly Patients ◽  
Half Life ◽  
Population Based ◽  
Once Daily ◽  
Nonlinear Mixed Effects Model ◽  
Elimination Half Life ◽  
Healthy Elderly ◽  
Age Related ◽  
Elimination Half ◽  
Patients With Epilepsy

Phenytoin Half-Life and Clearance during Maintenance Therapy in Adults and Elderly Patients with Epilepsy. Ahn JE, Cloyd JC, Brundage RC, Marino SE, Conway JM, Ramsay RE, White JR, Musib LC, Rarick JO, Birnbaum AK, Leppik IE. Neurology 2008;71(1):38–43. BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients’ sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2–3 weeks.

Epidural, Cerebrospinal Fluid, and Plasma Pharmacokinetics of Epidural Opioids (Part 2)

2003 ◽  
Vol 99 (2) ◽  
pp. 466-475 ◽  
Author(s):  
Christopher M. Bernards ◽  
Danny D. Shen ◽  
Emily S. Sterling ◽  
Jason E. Adkins ◽  
Linda Risler ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Epidural Space ◽  
Drug Concentration ◽  
Half Life ◽  
Sampling Site ◽  
Pharmacokinetic Parameters ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Plasma Pharmacokinetics ◽  
Venous Plasma

Background The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. Methods Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. Results The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. Conclusions The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.

scholarly journals Azelastine and suplatast shorten the distribution half-life of IgE in rats

2002 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
Kazuhiko Hanashiro ◽  
Yoshihiro Tokeshi ◽  
Toshiyuki Nakasone ◽  
Masanori Sunagawa ◽  
Mariko Nakamura ◽  
...  
Keyword(s):  
Immunosorbent Assay ◽  
Rate Constants ◽  
Half Life ◽  
Wistar Rats ◽  
Immunoglobulin E ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pharmacokinetic Parameters ◽  
Distilled Water ◽  
Elimination Half Life ◽  
Elimination Half

We aim to clarify whether suplatast and azelastine (anti-allergic drugs) can shorten the half-life of immunoglobulin E (IgE) in the circulating blood. Thirty Wistar rats were divided into six groups. Distilled water or anti-allergic drugs were given orally for 6 days after the first sensitization. Two milligrams of monoclonal dinitrophenyl (DNP)-specific rat IgE was administered to the rats, which had been given suplatast or azelastine orally. The level of DNP-specific rat IgE in the serum was estimated by IgE-capture enzyme-linked immunosorbent assay, and the turnover of IgE was analyzed from its pharmacokinetic parameters. The elimination half-life of rat IgE was about 12 h irrespective of the sensitized state. The intercompartmental rate constants (KctandKtc) in the suplatast-administered or azelastine-administered group were larger than those of the distilled water-administered group under non-sensitized conditions. These findings suggested that the anti-allergic drugs used in the present study facilitated the excretion of IgE from the circulation in rats.

scholarly journals Activities of Dalbavancin In Vitro and in a Rabbit Model of Experimental Endocarditis Due to Staphylococcus aureus with or without Reduced Susceptibility to Vancomycin and Teicoplanin

2004 ◽  
Vol 48 (3) ◽  
pp. 1061-1064 ◽  
Author(s):  
Agnès Lefort ◽  
Juliette Pavie ◽  
Louis Garry ◽  
Françoise Chau ◽  
Bruno Fantin
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Half Life ◽  
Rabbit Model ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Once Daily ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACT For the treatment of rabbit endocarditis, dalbavancin given once daily (10 mg/kg of body weight for 4 days) or as a single 40-mg/kg dose was active against Staphylococcus aureus with or without reduced susceptibility to glycopeptides, as expected from its good in vitro activity, even in broth supplemented with 90% serum and given its prolonged elimination half-life.

scholarly journals Pharmacokinetics of Dolutegravir in a Premature Neonate after HIV Treatment Intensification during Pregnancy

2015 ◽  
Vol 59 (6) ◽  
pp. 3660-3662 ◽  
Author(s):  
J. B. Pain ◽  
M. P. Lê ◽  
M. Caseris ◽  
C. Amiel ◽  
L. Lassel ◽  
...  
Keyword(s):  
Half Life ◽  
Premature Neonate ◽  
Hiv Treatment ◽  
Efflux Transporter ◽  
Treatment Intensification ◽  
Once Daily ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACTWe describe the pharmacokinetics of dolutegravir (DTG) in a premature neonate after maternal intensification of an antiretroviral (ARV) regimen by adding DTG. During the last 2 weeks of pregnancy, the ARV was tenofovir-emtricitabine, atazanavir-ritonavir, and DTG (50 mg once daily). From the interaction between atazanavir and DTG via CYP3A4 and UGT1A1 and placental efflux transporter inhibition and considering the infant's probable enzymatic immaturity, the DTG elimination half-life was estimated to be 4-fold longer in neonates than in adults.

Measured Context-sensitive Half-times of Remifentanil and Alfentanil

1995 ◽  
Vol 83 (5) ◽  
pp. 968-975 ◽  
Author(s):  
Atul Kapila ◽  
Peter S. A. Glass ◽  
James R. Jacobs ◽  
Keith T. Muir ◽  
David J. Hermann ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Half Life ◽  
Computer Modelling ◽  
Constant Infusion ◽  
Pharmacokinetic Parameters ◽  
Half Time ◽  
Elimination Half Life ◽  
Context Sensitive ◽  
Elimination Half ◽  
True Time

Abstract Background The context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using known pharmacokinetic parameters. The modelled context-sensitive half-time for a 3-h infusion of alfentanil is 50–55 min and is 3 min for remifentanil. The terminal elimination half-life is 111 min for alfentanil and 12–30 min for remifentanil. It has not been tested whether the modelled context-sensitive half-time reflects the true time for a 50% decrease in drug concentration or drug effect.

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