scholarly journals Impact of efavirenz, ritonavir-boosted lopinavir and nevirapine based antiretroviral regimens on the pharmacokinetics of lumefantrine and safety of artemether-lumefantrine in falciparum-negative HIV-infected Malawian adults stabilized on antiretroviral therapy

2018 ◽  
Author(s):  
Clifford George Banda ◽  
Fraction Dzinjalamala ◽  
Mavuto Mukaka ◽  
Jane Mallewa ◽  
Victor Maiden ◽  
...  
Keyword(s):  
Safety Profile ◽  
Standard Dose ◽  
Time Curve ◽  
Therapeutic Implications ◽  
Antiretroviral Therapies ◽  
Concentration Time ◽  
Group I ◽  
Conflicting Evidence ◽  
Immunodeficiency Virus ◽  
The Impact

ABSTRACTThere is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve (AUC0-14 days) of lumefantrine and safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV) infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n = 6/group): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n = 10–15/group): (i) antiretroviral-naïve, (ii) on efavirenz-based ART and (iii) on ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine’s AUC0-14 days was 53% [95% CI: 0.27-0.82] lower in the efavirenz-based ART group than the ART-naïve group and was 2.4 [95% CI: 1.58-3.62] and 2.9 [95% CI: 1.75-4.72] times higher in the nevirapine and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine’s AUC0-14 days was 1.9 [95% CI: 1.26-3.00] times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz-and ART-naïve groups (0.99 [95% CI: 0.63-1.57]). Frequent cases of haematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria co-infected adults.

scholarly journals Impact of Efavirenz-, Ritonavir-Boosted Lopinavir-, and Nevirapine-Based Antiretroviral Regimens on the Pharmacokinetics of Lumefantrine and Safety of Artemether-Lumefantrine inPlasmodium falciparum-Negative HIV-Infected Malawian Adults Stabilized on Antiretroviral Therapy

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Clifford G. Banda ◽  
Fraction Dzinjalamala ◽  
Mavuto Mukaka ◽  
Jane Mallewa ◽  
Victor Maiden ◽  
...  
Keyword(s):  
Safety Profile ◽  
Standard Dose ◽  
Time Curve ◽  
Therapeutic Implications ◽  
Group I ◽  
Conflicting Evidence ◽  
Immunodeficiency Virus ◽  
Hematological Abnormalities ◽  
Clinical Trials Registry ◽  
The Impact

ABSTRACTThere is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and the safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve from 0 h to 14 days (AUC0–14 days) of lumefantrine and the safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV)-infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n= 6/group): (i) antiretroviral naive, (ii) nevirapine-based ART, (iii) efavirenz-based ART, and (iv) ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n= 10 to 15/group): (i) antiretroviral naive, (ii) efavirenz-based ART, and (iii) ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine's AUC0–14 dayswas 53% (95% confidence interval [CI], 0.27 to 0.82) lower in the efavirenz-based ART group than in the ART-naive group and was 2.4 (95% CI, 1.58 to 3.62) and 2.9(95% CI, 1.75 to 4.72) times higher in the nevirapine- and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine's AUC0–14 dayswas 1.9 (95% CI, 1.26 to 3.00) times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz- and ART-naive groups (0.99 [95% CI, 0.63 to 1.57]). Frequent cases of hematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria-coinfected adults. (This study has been registered at the Pan African Clinical Trials Registry under numbers PACTR2010030001871293 and PACTR2010030001971409.)

scholarly journals Multidose Pharmacokinetics of Ritonavir and Zidovudine in Human Immunodeficiency Virus-Infected Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1788-1793 ◽  
Author(s):  
Allen Cato ◽  
Jiang Qian ◽  
Ann Hsu ◽  
Benjamin Levy ◽  
John Leonard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Adverse Event ◽  
Dosage Adjustment ◽  
Elimination Rate ◽  
Time Curve ◽  
Safety And Efficacy ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Asymptomatic Human Immunodeficiency Virus

ABSTRACT The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h]) alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (C max) of ZDV plasma decreased from 748 ± 375 (mean ± standard deviation) to 546 ± 296, and area under the concentration-time curve from 0 to 24 h (AUC0–24) decreased from 3,052 ± 1,007 to 2,261 ± 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide C max and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3′-amino-3′-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.

scholarly journals Pharmacokinetics of zidovudine after rectal administration in human immunodeficiency virus-infected patients.

1997 ◽  
Vol 41 (5) ◽  
pp. 1143-1145 ◽  
Author(s):  
U Wintergerst ◽  
B Rolinski ◽  
J R Bogner ◽  
G Notheis ◽  
F D Goebel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Intake ◽  
Pharmacokinetic Profile ◽  
Rectal Administration ◽  
Beta Phase ◽  
Time Curve ◽  
Concentration Time ◽  
Release Device ◽  
Immunodeficiency Virus ◽  
The Mean

We evaluated the pharmacokinetics of rectally administered zidovudine (ZDV) in 10 human immunodeficiency virus-infected adults. After rectal administration of an aqueous ZDV solution (250 mg of ZDV), mean peak ZDV levels were 1.3 +/- 0.7 micromol/liter (mean +/- standard deviation) versus 5.0 +/- 2.2 micromol/liter (P < 0.0001) after oral intake of a 250-mg ZDV capsule. The half-life at beta phase was 87.8 +/- 39.6 min for rectally administered ZDV versus 55.8 +/- 20.1 min (P = 0.035) for orally administered ZDV. The mean area under the concentration-time curve from 0 min to infinity was 232 +/- 181 micromol/liter x min after rectal administration versus 362 +/- 110 micromol/liter x min after oral intake. Although the two routes were not bioequivalent, ZDV was absorbed considerably after rectal administration, with a pharmacokinetic profile resembling that of a sustained-release device.

scholarly journals Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

2003 ◽  
Vol 47 (1) ◽  
pp. 118-123 ◽  
Author(s):  
Cecile Goujard ◽  
Isabelle Vincent ◽  
Jean-Luc Meynard ◽  
Nathalie Choudet ◽  
Diane Bollens ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Hiv 1

ABSTRACT The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 μg · h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

scholarly journals Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

2009 ◽  
Vol 53 (10) ◽  
pp. 4407-4413 ◽  
Author(s):  
Déborah Hirt ◽  
Saik Urien ◽  
Mathieu Olivier ◽  
Hélène Peyrière ◽  
Boubacar Nacro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Plasma Concentrations ◽  
Individual Characteristics ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C mins below 1 mg/liter. A significantly higher percentage of children with C mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

scholarly journals Effect of Rifampin on Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Healthy Volunteers

2006 ◽  
Vol 50 (10) ◽  
pp. 3336-3342 ◽  
Author(s):  
D. M. Burger ◽  
S. Agarwala ◽  
M. Child ◽  
A. Been-Tiktak ◽  
Y. Wang ◽  
...  
Keyword(s):  
Steady State ◽  
Standard Of Care ◽  
Hiv Protease ◽  
Control Group ◽  
Hiv Protease Inhibitors ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Dosing Regimens ◽  
Grade 3

ABSTRACT Mycobacterium tuberculosis is a concern in patients with human immunodeficiency virus (HIV) infection. Rifampin (RIF), an agent used against M. tuberculosis, is contraindicated with most HIV protease inhibitors. Atazanavir (ATV) has clinical efficacy comparable to a standard of care regimen in naive patients and, when dosed with low-dose ritonavir (RTV), also in treatment-experienced patients. We evaluated here the safety and pharmacokinetics of ATV, resulting from three regimens of ATV, RTV, and RIF in 71 healthy subjects. The pharmacokinetics for ATV and RTV were assessed after 6 and 10 days of dosing with ATV 400 mg (n = 53) and with ATV-RTV at 300 and 100 mg (ATV/RTV 300/100; n = 52), respectively. Steady-state pharmacokinetics for ATV, RTV, RIF, and desacetyl-rifampin (des-RIF) were measured after 10 days of dosing of ATV/RTV/RIF 300/100/600 (n = 17), ATV/RTV/RIF 300/200/600 (n = 17), or ATV/RTV/RIF 400/200/600 (n = 14). An RIF 600-alone arm was enrolled as a control group (n = 18). With ATV/RTV/RIF 400/200/600, ATV area under the concentration-time curve values were comparable, but the C min values were lower relative to ATV 400 alone. ATV exposures were substantially reduced for the other RIF-containing regimens relative to ATV 400 alone and for all regimens relative to ATV/RTV 300/100 alone. RIF and des-RIF exposures were 1.6- to 2.5-fold higher than with RIF 600 alone. The incidence of grade 3/4 alanine aminotransferase/aspartate aminotransferase values was limited to 1 subject each in both the ATV/RTV/RIF 300/200/600 and the ATV/RTV/RIF 400/200/600 treatments. Coadministration of ATV with RIF was safe and generally well tolerated. Since ATV exposures were reduced in all regimens, ATV and RIF should not be coadministered at the dosing regimens studied.

scholarly journals Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors

2005 ◽  
Vol 49 (8) ◽  
pp. 3558-3561 ◽  
Author(s):  
Patrick F. Smith ◽  
Gregory K. Robbins ◽  
Robert W. Shafer ◽  
Hulin Wu ◽  
Song Yu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Half Life ◽  
Pharmacokinetic Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean

ABSTRACT Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

scholarly journals Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults

2011 ◽  
Vol 55 (7) ◽  
pp. 3240-3243 ◽  
Author(s):  
Aaron M. Cook ◽  
Craig Martin ◽  
Val R. Adams ◽  
R. Scott Morehead
Keyword(s):  
Standard Dose ◽  
Normal Weight ◽  
Serum Concentrations ◽  
Serum Samples ◽  
Obese Adults ◽  
Time Curve ◽  
Physiochemical Properties ◽  
Concentration Time ◽  
Optimal Dosing ◽  
Serial Serum

ABSTRACTThe physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

The impact of missing values in the concentration-time curve on the assessment of bioequivalence

2005 ◽  
Vol 4 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Allan Donner ◽  
Walter W. Hauck ◽  
Guangyong Zou
Keyword(s):  
Missing Values ◽  
Time Curve ◽  
Concentration Time ◽  
The Impact

scholarly journals Rifampin Reduces Concentrations of Trimethoprim and Sulfamethoxazole in Serum in Human Immunodeficiency Virus-Infected Patients

2001 ◽  
Vol 45 (11) ◽  
pp. 3238-3241 ◽  
Author(s):  
Esteban Ribera ◽  
Leonor Pou ◽  
Antoni Fernandez-Sola ◽  
Francisco Campos ◽  
Rosa M. Lopez ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance Liquid Chromatography ◽  
High Performance ◽  
Parent Drug ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Antituberculosis Treatment ◽  
Immunodeficiency Virus ◽  
Before And After

ABSTRACT To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co-trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC0–24), respectively, were observed after administration of rifampin.N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC0–24 metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients.

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