scholarly journals Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Frantz Foissac ◽  
Jörn Blume ◽  
Jean-Marc Tréluyer ◽  
Thorkild Tylleskär ◽  
Chipepo Kankasa ◽  
...  
Keyword(s):  
South African ◽  
Population Analysis ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Breastfed Infants ◽  
Trough Concentrations ◽  
Therapeutic Doses ◽  
Mother To Child ◽  
Hiv 1

ABSTRACT The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain values above the therapeutic pharmacokinetic targets in most infants. (This study has been registered at ClinicalTrials.gov under identifier NCT00640263.)

Operational effectiveness and 36 week HIV-free survival in the South African programme to prevent mother-to-child transmission of HIV-1

AIDS ◽  
2007 ◽  
Vol 21 (4) ◽  
pp. 509-516 ◽  
Author(s):  
Debra J Jackson ◽  
Mickey Chopra ◽  
Tanya M Doherty ◽  
Mark SE Colvin ◽  
Jonathan B Levin ◽  
...  
Keyword(s):  
South African ◽  
Mother To Child Transmission ◽  
Child Transmission ◽  
The South ◽  
Operational Effectiveness ◽  
Free Survival ◽  
Mother To Child ◽  
Hiv 1

scholarly journals Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

2004 ◽  
Vol 48 (11) ◽  
pp. 4328-4331 ◽  
Author(s):  
Robert DiCenzo ◽  
Derick Peterson ◽  
Kim Cruttenden ◽  
Gene Morse ◽  
Garret Riggs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Valproic Acid ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

Exposure to chloroquine in male adults and children aged 9–11 years with malaria due to Plasmodium vivax

2020 ◽  
Author(s):  
Michelle Valeria Dias Ferreira Vieira ◽  
José Luiz Fernandes Vieira
Keyword(s):  
Plasmodium Vivax ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Time Profile ◽  
Pharmacokinetic Parameters ◽  
Older Children ◽  
Asexual Blood Stage ◽  
Adults And Children ◽  
A Prospective Study

Abstract Background Chloroquine is effective against the asexual blood stage of Plasmodium vivax. A high proportion of children are underdosed with the drug, but there are no studies comparing chloroquine exposure in adults and children aged 8–11 years old. The present study intends to compare these populations using the area under the curve (AUC) derived from the plasma concentration-time profile in patients with P. vivax. Methods A prospective study of cases was performed on male children (aged 9–11 years) and adults with vivax malaria. Blood samples were collected after several days of treatment. Chloroquine was measured by high-performance liquid chromatography. A non-compartmental pharmacokinetic model was used to calculate the pharmacokinetic parameters of the drug. Results A total of 20 children and 25 adults were included in the study. Plasma concentrations of chloroquine in older children ranged from 67 to 1112 ng/ml, and in adults the value ranged from 74 to 1147 ng/ml. The AUC to the last measurable concentration and to infinite was significantly lower in children than in adults, indicating a lower exposure to the drug. Conclusion These data demonstrate lower exposure to chloroquine in children, which corroborates the importance of optimising the doses of chloroquine in the study age band to ensure adequate exposure to the drug.

scholarly journals Vancomycin Dosing and Pharmacokinetics in Postoperative Pediatric Cardiothoracic Surgery Patients

2016 ◽  
Vol 21 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Emily C. Benefield ◽  
Tracy M. Hagemann ◽  
H. Christine Allen ◽  
Kevin Farmer ◽  
Michael E. Burton ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Primary Objective ◽  
Cardiothoracic Surgery ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Future Prospective Study ◽  
Trough Concentrations ◽  
High Degree

OBJECTIVES: This study compared vancomycin trough concentrations and pharmacokinetic parameters in pediatric cardiothoracic surgery (CTS) patients versus those in controls receiving 20 mg/kg/dose, intravenously, every 8 hours. METHODS: A retrospective study was conducted in children <18 years of age, following CTS, versus an age-and sex-matched control group. The primary objective was to determine differences in trough concentrations between groups. Secondary objectives included comparisons of pharmacokinetics between groups and development of vancomycin-associated acute kidney injury (AKI), defined as a doubling in serum creatinine from baseline. Also dosing projections were developed to target an area-under-the-curve-to-minimum inhibitory concentration (AUC:MIC) ratio of ≥400. RESULTS: Twenty-seven patients in each group were evaluated. Mean trough concentrations were significantly different between groups (CTS: 18.4 mg/L; control: 8.8 mg/L; p < 0.01). Vancomycin-associated acute kidney injury AKI was significantly higher in the CTS group than in controls (25.9% versus 0%, respectively, p<0.01). There were significant differences in vancomycin elimination rates, with a high degree of variability, but no statistical differences in other parameters. Based on dosing projections, CTS patients would require 21 to 88 mg/kg/day, with a dosage interval determined by the child's glomerular filtration rate to achieve the target AUC:MIC ≥400. CONCLUSIONS: Vancomycin dosage of 20 mg/kg/dose intravenously every 8 hours achieved significantly higher trough concentrations in CTS patients than in controls. Pharmacokinetic parameters were highly variable in CTS patients, indicating more individualization of dosage is needed. A future prospective study is needed to determine whether the revised dosage projections achieve the AUC:MIC target and to determine whether these regimens are associated with less vancomycin-associated AKI.

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients

2018 ◽  
Vol 34 (10) ◽  
pp. 1766-1772 ◽  
Author(s):  
Lama M Hsaiky ◽  
Francine D Salinitri ◽  
Judy Wong ◽  
Sin-Ling T Jennings ◽  
Neha H Desai ◽  
...  
Keyword(s):  
Half Life ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Optimal Dose ◽  
Hemodialysis Patients ◽  
Pharmacokinetic Parameters ◽  
Intermittent Hemodialysis ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Serious Adverse Events

Abstract Background Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. Methods This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. Results Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean ±standard deviation (SD) elimination half-life of 19.3 ±6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343±48 µg/mL postdose. The mean ±SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2±0.5 mL/min and 3295±1187 mL, respectively. The area under the curve for 0 h–∞ (AUCinf) was 7494 ±1424 h•µg/mL. No gender effect was observed and no serious adverse events were reported. Conclusions Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.

Phase I clinical and pharmacokinetic study of oral etoposide phosphate.

1995 ◽  
Vol 13 (1) ◽  
pp. 200-209 ◽  
Author(s):  
C Sessa ◽  
M Zucchetti ◽  
T Cerny ◽  
O Pagani ◽  
F Cavalli ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Administration ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Oral Etoposide ◽  
Validation Data ◽  
Etoposide Phosphate

PURPOSE To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.

scholarly journals Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 438
Author(s):  
Adela-Nicoleta Roşian ◽  
Ştefan Horia Roşian ◽  
Bela Kiss ◽  
Maria Georgia Ştefan ◽  
Adrian Pavel Trifa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Plasma Level ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Real Life ◽  
Pharmacokinetic Parameters ◽  
Liquid Chromatography Tandem Mass ◽  
Trough Concentrations ◽  
Abcb1 Genotype

(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The ABCB1 genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban’s plasma level and to establish if a certain relationship has clinical relevance. (2) Methods: Fifty-three NVAF patients were treated with 5 mg apixaban twice/day (70.0 years, range: 65–77, 60.4% men). Trough and peak plasma concentrations of apixaban were determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS), and ABCB1 genotyping was performed. (3) Results: Apixaban plasma concentrations varied considerably. They were higher in women than in men (311.2 ng/dL vs. 252.2 ng/dL; p = 0.05) and were lower in patients with heart failure (149.4 ng/dL vs. 304.5 ng/dL; p < 0.01). Creatinine clearance was inversely correlated with the apixaban plasma level (Spearman correlation: r = −0.365; p = 0.007 for trough concentrations). No statistically significant differences between the genotypic groups of ABCB1 rs1045642 and ABCB1 rs4148738 were found in the trough or peak apixaban plasma concentrations. (4) Conclusions: Pharmacokinetic parameters are influenced by several clinical factors of which renal function is the major determinant. Plasma concentrations measured in women had higher values than those measured in men, and heart failure was associated with decreased plasma levels of apixaban.

scholarly journals HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients

2016 ◽  
Vol 60 (10) ◽  
pp. 6050-6059 ◽  
Author(s):  
Neesha Rockwood ◽  
Graeme Meintjes ◽  
Maxwell Chirehwa ◽  
Lubbe Wiesner ◽  
Helen McIlleron ◽  
...  
Keyword(s):  
Body Weight ◽  
Antiretroviral Therapy ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
World Health ◽  
Pharmacokinetic Parameters ◽  
Antituberculosis Drug ◽  
Antituberculosis Treatment ◽  
Drug Concentrations ◽  
Hiv 1

ABSTRACTThere are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0–24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0–24. The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients.

scholarly journals Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

2010 ◽  
Vol 54 (10) ◽  
pp. 4424-4431 ◽  
Author(s):  
K. Han ◽  
B. Capitano ◽  
R. Bies ◽  
B. A. Potoski ◽  
S. Husain ◽  
...  
Keyword(s):  
Lung Transplant ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Early Postoperative Period ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Transplant Patients ◽  
Postoperative Time ◽  
Trough Concentrations ◽  
Oral Doses

ABSTRACT This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R 2 = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC0-∞) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, Vc , and Vp were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. Vp increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.

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