Dolutegravir pharmacokinetics during co-administration with either artemether/lumefantrine or artesunate/amodiaquine

2021 ◽  
Author(s):  
Aida N Kawuma ◽  
Stephen I Walimbwa ◽  
Goonaseelan (Colin) Pillai ◽  
Saye Khoo ◽  
Mohammed Lamorde ◽  
...  
Keyword(s):  
Day Treatment ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Sub Saharan Africa ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Two Phase ◽  
Transit Compartment ◽  
First Line Therapy ◽  
Sub Saharan

Abstract Background In sub-Saharan Africa, artemisinin-containing therapies for malaria treatment are regularly co-administered with ART. Currently, dolutegravir-based regimens are recommended as first-line therapy for HIV across most of Africa. Objectives To investigate the population pharmacokinetics of dolutegravir during co-administration with artemether/lumefantrine or artesunate/amodiaquine, two commonly used antimalarial therapies. Methods We developed a population pharmacokinetic model of dolutegravir with data from 26 healthy volunteers in two Phase 2 studies with a total of 403 dolutegravir plasma concentrations at steady state. Volunteers received 50 mg of dolutegravir once daily alone or in combination with standard treatment doses of artemether/lumefantrine (80/480 mg) or artesunate/amodiaquine (200/540 mg). Results A two-compartment model with first-order elimination and transit compartment absorption best described the concentration–time data of dolutegravir. Typical population estimates for clearance, absorption rate constant, central volume, peripheral volume and mean absorption transit time were 0.713 L/h, 1.68 h−1, 13.2 L, 5.73 L and 1.18 h, respectively. Co-administration of artemether/lumefantrine or artesunate/amodiaquine increased dolutegravir clearance by 10.6% (95% CI 4.09%–34.5%) and 26.4% (95% CI 14.3%–51.4%), respectively. Simulations showed that simulated trough concentrations of dolutegravir alone or in combination with artemether/lumefantrine or artesunate/amodiaquine are maintained above the dolutegravir protein-adjusted IC90 of 0.064 mg/L for more than 99% of the individuals. Conclusions Dolutegravir dose adjustments are not necessary for patients who are taking standard 3 day treatment doses of artemether/lumefantrine or artesunate/amodiaquine.

scholarly journals Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers

2020 ◽  
Author(s):  
Andy R. Eugene
Keyword(s):  
Clinical Study ◽  
Tissue Distribution ◽  
Trough Level ◽  
Day Treatment ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Time Data ◽  
Human Lung Cells

AbstractBackgroundRecent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pathogen and one clinical study reported fluoxetine exposure at a median dose of 20mg in patients with the SARS-Cov-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-Cov-2 as reported in Calu-3 human lung cells.MethodsPopulation pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption was used to simulate fluoxetine concentration-time data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20mg/day, 40mg/day, and 60mg/day) to estimate the percentage of the patients achieving a trough level for the EC90 SARS-Cov-2 inhibitory concentration at each day throughout a 10-day treatment period. All analyses were conducted via statistical programming in R.ResultsStandard fluoxetine antidepressant doses resulted in a range of 79% to 97% of the patient population achieving a trough target plasma concentration of 25.1 ng/ml which translates to lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 μM). At a dose of 40mg per day, at least 85% of patients will reach the trough target EC90 concentration within 3-days. The findings of this pharmacokinetic dosing study corroborate both in vitro and observational clinical study findings showing fluoxetine inhibits the SARS-Cov-2 pathogen at commonly treated doses in the practice of psychiatry.

scholarly journals Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 477
Author(s):  
Andy R. Eugene
Keyword(s):  
Tissue Distribution ◽  
Day Treatment ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Human Lung Cells ◽  
Retrospective Clinical Study ◽  
Target Plasma Concentration

Background.  Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K, K417N, N501Y), and one retrospective clinical study reported fluoxetine exposure at a median dose of 20 mg in patients with the SARS-CoV-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-CoV-2 as reported in Calu-3 human lung cells.  Methods.  Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption were used to simulate fluoxetine pharmacokinetic data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20 mg/day, 40 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC90 SARS-CoV-2 inhibitory concentration for a 10 day treatment period. All analyses were conducted via statistical programming in R.  Results.  Standard fluoxetine antidepressant doses resulted in a range of 81% to 97% of the patient population achieving a trough target plasma concentration of 23.2 ng/ml at day 10 and translates to a lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 mM). At a dose of 40 mg per day, at least 87% of patients will reach the trough target EC90 concentration within three days.   Conclusion. Overall, the findings of this population pharmacokinetic dosing study corroborates in vitro and observational clinical studies reporting the first selective serotonin reuptake inhibitor fluoxetine inhibits the SARS-CoV-2 pathogen at commonly treated doses in the practice of psychiatry.

scholarly journals Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5314-5324 ◽  
Author(s):  
Almudena Sánchez ◽  
Salvador Cabrera ◽  
Dolores Santos ◽  
M. Paz Valverde ◽  
Aurelio Fuertes ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Mixed Effect ◽  
Factors Affecting ◽  
Nonlinear Mixed Effect ◽  
Study Population ◽  
Major Factors

ABSTRACTDespite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

scholarly journals Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers

2018 ◽  
Vol 128 (6) ◽  
pp. 1107-1116
Author(s):  
Josh D. Kaullen ◽  
Joel S. Owen ◽  
Kim L. R. Brouwer ◽  
Paul M. Heerdt ◽  
Cynthia A. Lien ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Blocking Agent ◽  
Rapid Onset ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agent ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Muscle Twitch ◽  
Concentration Data ◽  
Duration Of Action

Abstract Background CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. Methods Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose–response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. Results A four-compartment model was fit to the concentration–time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. Conclusions CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

scholarly journals Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
A young J. Park ◽  
Joshua Wang ◽  
Jordanna Jayne ◽  
Lynn Fukushima ◽  
Adupa P. Rao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dosage Form ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Published Data ◽  
Total Clearance ◽  
Content Type ◽  
Complicated Skin

ABSTRACT Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs.

scholarly journals Assessment of the nlmixr R-package for population pharmacokinetic modeling: A metformin case study

2021 ◽  
Author(s):  
Wen Yao Mak ◽  
Qing Xi Ooi ◽  
Cintia Cruz ◽  
Irene Looi ◽  
Kah Hay Yuen ◽  
...  
Keyword(s):  
Compartment Model ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Mixed Effect ◽  
Flip Flop ◽  
Final Model ◽  
Elimination Phase ◽  
Transit Compartment ◽  
Terminal Elimination Phase

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

scholarly journals Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

2018 ◽  
Vol 62 (7) ◽  
pp. e02359-17 ◽  
Author(s):  
Michael A. Lyons
Keyword(s):  
Geometric Mean ◽  
Late Phase ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Clinical Testing ◽  
Half Maximum ◽  
Two Phase ◽  
Fed State

ABSTRACTPretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 ± 0.2 liters/h and 130 ± 5 liters, respectively, and the posterior population geometric mean for the half-maximum-effect dose for the reduction of bioavailability was 450 ± 50 mg. Interindividual variability, described by the percent coefficient of variation, was 32% ± 3% for clearance, 17% ± 4% for the volume of distribution, and 74% ± 9% for the half-maximum-effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

2016 ◽  
Vol 33 (S1) ◽  
pp. S572-S572
Author(s):  
J. Llaudó ◽  
L. Anta ◽  
I. Ayani ◽  
J. Martínez-González ◽  
I. Gutierro ◽  
...  
Keyword(s):  
Steady State ◽  
Dopamine D2 Receptor ◽  
Plasma Concentrations ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Population Pharmacokinetic Modeling ◽  
Population Pk ◽  
Long Acting

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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