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 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 Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects

2009 ◽  
Vol 53 (4) ◽  
pp. 1532-1538 ◽  
Author(s):  
Graeme Moyle ◽  
Marta Boffito ◽  
Carl Fletcher ◽  
Chris Higgs ◽  
Phillip E. Hay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Virologic Suppression ◽  
Open Label ◽  
Time Curve ◽  
Mixed Effect ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
And Gender

ABSTRACT Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC0-24) and comparable CBV-TP concentrations at the end of the dosing interval (C τ). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C max) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC0-24 and 99% higher CBV-TP C max than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC0-24 and 81% higher weight-adjusted CBV-TP AUC0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C τ values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

Pharmacokinetics and Dose-Finding of Fragmin in Pediatric Patients at Risk for Thromboembolic Events.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1861-1861
Author(s):  
Lesley G. Mitchell ◽  
Patricia Massicotte ◽  
Patricia Vegh ◽  
Peter Cox ◽  
Dimple Patel ◽  
...  
Keyword(s):  
Age Groups ◽  
Dose Finding ◽  
Pharmacokinetic Parameters ◽  
Renal Ultrasound ◽  
Maximum Plasma ◽  
Thromboembolic Events ◽  
Bleeding Events ◽  
Mixed Effect ◽  
Once Daily ◽  
Increased Risk

Abstract BACKGROUND: Low-molecular-weight heparins are increasingly being used for prophylaxis of thromboembolic events (TE) in children. Fragmin offers the advantage of once-daily dosing. However appropriate dosing and pharmacokinetics (PK) of Fragmin in children are unknown. The objective of the study was to determine once daily dose of Fragmin required in children to achieve anti-Xa levels of 0.10–0.40 Anti-Xa U/mL. PK of Fragmin over all age groups. STUDY DESIGN: Prospective cohort study in non-selected children at increased risk for TE who were being treated at Stollery Children’s Hospital, Edmonton or Hospital for Sick Children, Toronto, Canada. All children received a starting dose of 100 mg/kg, an Anti-Xa level was drawn 4 hours post and dosages were adjusted until the target 0.1–0.4 μ/ml was reached. Children then entered the pharmacokinetic phase and blood was drawn at specified timepoints over several different days for Anti-Xa levels. A sparse sampling scheme and population-based, nonlinear mixed effect model approach were used to assess exposure targets. The primary outcomes were: dose required to achieve therapeutic anti-Xa levels in each of the age groups. observed maximum plasma activity (Cmax), time that Cmax was observed (Tmax), half-life (t1/2) and extravascular plasma clearance (Cl/F). Safety was assessed by collection of data on bleeding and thrombotic events. RESULTS: 43 children were enrolled, 1 developed a TE prior to receiving Fragmin 42 received drug. Two patients developed TE after one dose, 5 withdrew voluntarily and 1 had CVL removed early. 34 received the drug, 31 contributed PK data. A once compartment model with allometrically-scaled clearance and volume best explained observed concentration-time profiles. The median maintenance dose in children under 5 yrs of age was 100 IU/Kg whereas 5–10 and 10–16 yr old required 88 and 63 IU/Kg respectfully. The PK parameters are summarised in Table I. In terms of safety, there were no major bleeding events reported. Minor bleeds were reported in 4 patients: 3 bleeding at insuflon site and 1 oozing from PICC line. Two patients had asymptomatic thrombosis discovered on chance finding: 1 patient with a portal vein thrombosis discovered on routine renal ultrasound which did not resolve on treatment. One patient had a small clot at tip of CVL discovered on routine echocardiogram which did resolve on treatment. CONCLUSIONS: Dosing of Fragmin is age-dependent. The PK studies showed an increase in clearance of Fragmin in younger children. The volume of distribution is approximately equal to plasma volume and remains constant across the studied age ranges. The shift in time to maximum Anti-Xa level maybe due to absorption-related differences which means the 4-hour sampling paradigm is not adequate to judge therapeutic exposure across age groups. Table I: Pharmacokinetic parameters 0−2 months (n=6) 2–12 Months (n=8) 1−5 Years (n=6) 5−10 years (n=4) 10–16 years (n=7) Cmax [IU/mL] 0.13 0.26 0.26 0.29 0.34 Tmax [hours] 1.6 1.8 2.1 2.3 2.6 T1.2 [hours] 0.50 0.61 0.77 0.90 1.08 CL/F [L/hour/kg] 0.046 0.032 0.031 0.024 0.019

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.

scholarly journals Impact of cyp51A Mutations on the Pharmacokinetic and Pharmacodynamic Properties of Voriconazole in a Murine Model of Disseminated Aspergillosis

2010 ◽  
Vol 54 (11) ◽  
pp. 4758-4764 ◽  
Author(s):  
Eleftheria Mavridou ◽  
Roger J. M. Bruggemann ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
Johan W. Mouton
Keyword(s):  
Murine Model ◽  
Maximum Effect ◽  
Wild Type ◽  
Time Curve ◽  
Unbound Fraction ◽  
Once Daily ◽  
Type Population ◽  
Disseminated Aspergillosis ◽  
Wild Type Control

ABSTRACT The in vivo efficacy of voriconazole against 4 clinical Aspergillus fumigatus isolates with MICs ranging from 0.125 to 2 mg/liter (CLSI document M38A) was assessed in a nonneutropenic murine model of disseminated aspergillosis. The study involved TR/L98H, M220I, and G54W mutants and a wild-type control isolate. Oral voriconazole therapy was started 24 h after intravenous infection of mice and was given once daily for 14 consecutive days, with doses ranging from 10 to 80 mg/kg of body weight, using survival as the endpoint. Survival for all isolates was dependent on the voriconazole dose level (R 2 value of 0.5 to 0.6), but a better relationship existed for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) or the AUC for the free, unbound fraction of the drug divided by the MIC (fAUC/MIC ratio) (R 2 value of 0.95 to 0.98). The 24-h fAUC/MIC ratio showed a clear relationship to effect, with an exposure index for amount of free drug required for 50% of maximum effectiveness (fEI50) of 11.17 at day 7. Maximum effect was reached at values of around 80 to 100, comparable to that observed for posaconazole and A. fumigatus. Mice infected with an isolate having a MIC of 2 mg/liter required an exposure that was inversely correlated with the increase in MIC compared to that of the wild-type control, but due to nonlinear pharmacokinetics, this required only doubling of the voriconazole dose. The efficacy of voriconazole for isolates with high MICs for other triazoles but voriconazole MICs within the wild-type population range was comparable to that for the wild-type control. Finally, we used a grapefruit juice-free murine model of aspergillosis and concluded that this model is appropriate to study pharmacokinetic/pharmacodynamic relationships of voriconazole.

scholarly journals Effect of Fluconazole on Indinavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Patients

1998 ◽  
Vol 42 (2) ◽  
pp. 223-227
Author(s):  
S. De Wit ◽  
M. Debier ◽  
M. De Smet ◽  
J. McCrea ◽  
J. Stone ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Treatment Period ◽  
Geometric Mean ◽  
Pharmacokinetic Interaction ◽  
Hiv Protease ◽  
Pharmacokinetic Parameters ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
Clinically Significant ◽  
To Receive

ABSTRACT To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 7 1 3 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma ( C max ) and the time to reach C max were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally ( P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC 0–8 ) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases in C max and the concentration at 8 h postdosing ( C 8 ) were not as great as the decrease in AUC 0–8 . Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically ( P > 0.5) or clinically significant effect on the C max and C 8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT&gt;MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

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