Comparison of three galenic forms of lamivudine in young West African children living with Human Immunodeficiency Virus

2021 ◽  
pp. 135965352110582
Author(s):  
Claire Pressiat ◽  
Evelyne Dainguy ◽  
Jean-Marc Tréluyer ◽  
Caroline Yonaba ◽  
Saik Urien ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Target Population ◽  
West African ◽  
Pharmacokinetic Data ◽  
Liquid Formulation ◽  
Tablet Form ◽  
Two Compartment Model ◽  
Immunodeficiency Virus ◽  
Galenic Form

Background Few pharmacokinetic data were reported on dispersible tablets despite their increasing use. One hundred fifty HIV-infected children receiving lamivudine were enrolled in the MONOD ANRS 12,206 trial. Three galenic forms were administered: liquid formulation, tablet form and dispersible scored tablet. Method HIV-infected children <4 years old were enrolled in the MONOD ANRS 12,206 trial designed to assess the simplification of a successful 12-months lopinavir-based antiretroviral treatment with efavirenz. Lamivudine plasma concentrations were analysed using nonlinear mixed effects modelling approach. Results One hundred and fifty children (age: 2.5 years (1.9–3.2), weight 11.1 (9.5–12.5) kg (median (IQR)) were included in this study. Over the study period, 79 received only the syrup form, 29 children switched from syrup form to tablet 3TC/AZT form, 36 from syrup to the orodispersible ABC/3TC form and two from the 3TC/AZT form to the orodispersible ABC/3TC form. The 630 lamivudine concentrations were best described by a two-compartment model allometrically scaled. Galenic form had no significant effect on 3TC pharmacokinetic. Conclusion This trial provided an opportunity to compare three galenic forms (liquid formulation, tablet form and dispersible scored tablet) of lamivudine in the target population of young HIV–1-infected children. Galenic form had no significant effect on lamivudine pharmacokinetics.

scholarly journals Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

2007 ◽  
Vol 51 (5) ◽  
pp. 1822-1826 ◽  
Author(s):  
Olanrewaju Okusanya ◽  
Alan Forrest ◽  
Robin DiFrancesco ◽  
Sanela Bilic ◽  
Susan Rosenkranz ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Secondary Peak ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Healthy Human ◽  
Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

scholarly journals Clofazimine pharmacokinetics in patients with TB: dosing implications

2020 ◽  
Vol 75 (11) ◽  
pp. 3269-3277 ◽  
Author(s):  
Mahmoud Tareq Abdelwahab ◽  
Sean Wasserman ◽  
James C M Brust ◽  
Neel R Gandhi ◽  
Graeme Meintjes ◽  
...  
Keyword(s):  
Body Fat ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Drug Resistant ◽  
Elimination Half ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Fat Fraction

Abstract Background Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

Placental drug transfer in near-term ewes: acetylsalicylic and salicylic acid

1984 ◽  
Vol 62 (4) ◽  
pp. 441-445 ◽  
Author(s):  
J. J. Thiessen ◽  
R. B. Salama ◽  
F. Coceani ◽  
P. M. Olley
Keyword(s):  
Salicylic Acid ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Distribution Space ◽  
Irreversible Inhibitor ◽  
Fetal Plasma ◽  
Two Compartment Model ◽  
The Mean ◽  
Near Term ◽  
Thin Layer Chromatographic Analysis

Radiolabelled acetylsalicylic acid (ASA) and salicylic acid (SA) were given intravenously to four near-term ewes and their occurrence in both maternal and fetal plasma was ascertained using a specific thin-layer chromatographic analysis procedure. Findings proved that ASA and SA cross the placental barrier and reach distribution equilibrium about 40 min after salicylate administration. The equilibrium plasma fetal/maternal ratio for both salicylates averaged 0.4. Plasma concentrations of the two compounds in the mother and the fetus accorded with a two-compartment model having unusually large mean estimates (54 and 39 L) for the tissue distribution space of ASA and SA, respectively. Furthermore, the mean SA clearance in the ewe (358 mL∙min−1) was much greater than that reported in man, while the mean ASA clearance (764 mL∙min−1) was similar. Since ASA is an irreversible inhibitor of arachidonate cyclooxygenase, our findings reassert the need for caution in the use of the drug during pregnancy.

scholarly journals Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Didehydro-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys

1999 ◽  
Vol 43 (2) ◽  
pp. 381-384 ◽  
Author(s):  
Li Ma ◽  
Selwyn J. Hurwitz ◽  
Junxing Shi ◽  
Jeffrey J. McAtee ◽  
Dennis C. Liotta ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Rhesus Monkeys ◽  
Antiviral Agent ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Administration Route ◽  
Two Compartment Model ◽  
Immunodeficiency Virus ◽  
Median Effective Concentration

ABSTRACT The values of the pharmacokinetic parameters of the nucleoside antiretroviral agent β-d-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC) in rhesus monkeys were determined with a two-compartment model after the administration of a single dose. The average values for the terminal half-life, renal clearance, and total systemic clearance for the intravenous administration route were 3.6 h and 0.31 and 0.43 liter · kg−1 · h−1, respectively. The oral bioavailability of D-D4FC averaged 41%. For the intravenous administration route, 76% of the compound was recovered intact in the urine within 8 h, indicating that D-D4FC was eliminated mainly by renal excretion. D-D4FC was detected in the cerebrospinal fluid (CSF) at similar concentrations after administration by both the intravenous and oral routes. D-D4FC levels in plasma and CSF were higher than the median effective concentration for human immunodeficiency virus type 1 in vitro.

scholarly journals Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1690
Author(s):  
Idoia Bilbao-Meseguer ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Ana Alarcia-Lacalle ◽  
Alicia Rodríguez-Gascón ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Parameter Estimates ◽  
Population Modelling ◽  
Two Compartment Model ◽  
Relative Standard

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin.

1990 ◽  
Vol 8 (6) ◽  
pp. 1093-1100 ◽  
Author(s):  
A Rahman ◽  
J Treat ◽  
J K Roh ◽  
L A Potkul ◽  
W G Alvord ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Nausea And Vomiting ◽  
Maximum Plasma ◽  
Time Curve ◽  
Two Compartment Model ◽  
Major Organ ◽  
Free Doxorubicin ◽  
Clinical Verification ◽  
Moderate Nausea

We have treated 14 cancer patients with liposome-encapsulated doxorubicin (LED) at doses of 30, 45, 60, and 90 mg/m2. Nausea and vomiting, phlebitis, and stomatitis were minimal or absent at each dose, but dose-limiting granulocytopenia occurred at 90 mg/m2. Thrombocytopenia and/or anemia also occurred in all patients treated at 60 or 90 mg/m2. Complete alopecia was seen in one of three cases at 60 mg/m2 and all cases at 90 mg/m2. No hepatic, renal, or other major organ toxicities were encountered. Clinical cardiac toxicity did not occur in any patient, but the cumulative doxorubicin doses in 13 cases were less than 400 mg/m2. The plasma elimination of LED out to 24 hours was analyzed in terms of a two-compartment model. Depending upon the dose and the infusion time, maximum plasma concentrations ranged from 2.6 mumol/L to 36.89 mumol/L and the area under the plasma concentration x time curve (AUC) values ranged from 1.86 mumol/L x h/L to 49.57 mumol x h/L. These values are significantly higher than those expected for free doxorubicin. Urinary excretion of LED was approximately 10% after 24 hours. Doxorubicinol and doxorubicinone appeared at low levels in plasma 12 to 24 hours after injection. LED pharmacokinetics differ from those of free drug by the higher plasma levels and AUC of doxorubicin achieved, and by the low conversion of LED to metabolites. Overall, LED was well tolerated and produced only moderate nausea and vomiting and little stomatitis at myelosuppressive doses. The study also suggested that LED produces less venous sclerosis than free doxorubicin, but this requires further clinical verification.

scholarly journals Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Ashley M. Hopkins ◽  
Jessica Wojciechowski ◽  
Ahmad Y. Abuhelwa ◽  
Stuart Mudge ◽  
Richard N. Upton ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Delayed Release

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.

scholarly journals Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria Caused by Plasmodium vivax

2009 ◽  
Vol 53 (4) ◽  
pp. 1468-1475 ◽  
Author(s):  
Hyeong-Seok Lim ◽  
Jeong-Soo Im ◽  
Joo-Youn Cho ◽  
Kyun-Seop Bae ◽  
Terry A. Klein ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Prediction Interval ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Republic Of Korea ◽  
Mixed Effect ◽  
Two Compartment Model ◽  
Effect Of Treatment ◽  
The Republic

ABSTRACT Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.

scholarly journals O17 The bioavailability and maturing clearance of doxapram in preterm infants

2019 ◽  
Vol 104 (6) ◽  
pp. e8.1-e8 ◽  
Author(s):  
RB Flint ◽  
SHP Simons ◽  
P Andriessen ◽  
KD Liem ◽  
PLJ Degraeuwe ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Continuous Treatment ◽  
Population Pharmacokinetic ◽  
Two Compartment Model ◽  
Dosing Strategies ◽  
Vulnerable Patient ◽  
Apnea Of Prematurity

BackgroundDoxapram is used for intravenous and oral treatment of apnea of prematurity in preterm infants. Dosing is currently based on bodyweight, however pharmacokinetic and bioavailability data are limited. To develop individualized dosing strategies, we characterized pharmacokinetics of doxapram in this vulnerable patient population.MethodsData (302 samples) from 75 neonates were included with median (range) gestational age (GA) 25.9 (23.9–29.4) weeks, bodyweight 0.95 (0.48–1.61) kg, postnatal age (PNA) 17 (1–52) days at start of continuous treatment, and treatment duration of 16.8 (1.4–26.9) days. A population pharmacokinetic model was developed for doxapram and keto-doxapram.ResultsA two-compartment model best described the pharmacokinetics of doxapram and its metabolite. PNA and GA affected the formation clearance of keto-doxapram (CLD-KD) and clearance of doxapram via other routes (CLD). For an individual of 0.95 kg, GA of 25.9 weeks and PNA of 17 days, CLD-KD was 0.096 L/h (residual standard error (RSE) 22%) and CLD0.493 L/h (RSE 13%). Compared to PNA 30 days, estimated CLD-KD was 13% at PNA day 1 and 69% at day 15, and estimated CLD was 12% and 68%, respectively. Compared to GA 28 weeks, estimated CLD-KD was 65% at GA 24 weeks and 80% at 26 weeks, and estimated CLD was 67% and 81%, respectively. Oral bioavailability was estimated 74% (RSE 13%).ConclusionsWith bodyweight-based dosing alone, preterm infants with the lowest PNA and GA had relatively low doxapram CL and the highest exposure. Therefore, the dose may be reduced by 50% up to PNA day 9, and by 25% for day 10–15. In addition, for GA dose may be reduced by 40% and 20% in newborns with GA of 24–25 weeks and 26–27 weeks, respectively, compared to 28–29 weeks. For switch to oral therapy a 33% dose increase is required to maintain plasma concentrations.Disclosure(s)Nothing to disclose

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