scholarly journals Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women

2021 ◽  
Author(s):  
Wojciech Krzyzanski ◽  
Mark A. Milad ◽  
Alan H. Jobe ◽  
Thomas Peppard ◽  
Robert R. Bies ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Population Analysis ◽  
Plasma Concentrations ◽  
Estimation Method ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Indian Women ◽  
Dexamethasone Phosphate ◽  
Absorption Constant

AbstractPopulation analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability $${F}_{IM}$$ F IM . The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ($${CL/F}_{IM})$$ C L / F IM ) of 9.29 L/h, steady-state volume ($${{V}_{ss}/F}_{IM})$$ V ss / F IM ) of 56.4 L, IM absorption constant $$\left({k}_{aIM}\right)$$ k aIM of 0.460 1/h and oral absorption constant ($${k}_{aPO})$$ k aPO ) of 0.936 1/h. Betamethasone parameters were CL/FIM of 5.95 L/h, $${Vss/F}_{IM}$$ V s s / F IM of 72.4 L, $${k}_{aIM}$$ k aIM of 0.971 1/h, and $${k}_{aPO}$$ k aPO of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.

scholarly journals Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dong Liang ◽  
Jing Ma ◽  
Bo Wei
Keyword(s):  
Oral Dose ◽  
Oral Absorption ◽  
Jugular Vein ◽  
Plasma Concentrations ◽  
Pharmacokinetic Data ◽  
Simulated Weightlessness ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Interaction Kinetics ◽  
Kinetics Of

AbstractTo investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

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.

Evaluating the Accuracy of Using Population Pharmacokinetic Data to Predict Plasma Concentrations of Alfentanil

1988 ◽  
Vol 68 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Pierre O. Maitre ◽  
Max E. Ausems ◽  
Samuel Vozeh ◽  
Donald R. Stanski
Keyword(s):  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection

2006 ◽  
Vol 50 (11) ◽  
pp. 3801-3808 ◽  
Author(s):  
Sara Colombo ◽  
Thierry Buclin ◽  
Matthias Cavassini ◽  
Laurent A. Décosterd ◽  
Amalio Telenti ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Population Analysis ◽  
Pharmacokinetic Profile ◽  
Relative Bioavailability ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Genetic Traits

ABSTRACT Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1 (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.

scholarly journals 1561. Omadacycline Pharmacokinetics: Influence of Mortality Risk Score Among Patients with Community-Acquired Bacterial Pneumonia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S569-S570
Author(s):  
Elizabeth A Lakota ◽  
Lawrence Friedrich ◽  
Judith N Steenbergen ◽  
Paul C McGovern ◽  
Evan Tzanis ◽  
...  
Keyword(s):  
Bacterial Pneumonia ◽  
The United States ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Risk Class ◽  
Drug Plasma ◽  
Post Hoc ◽  
Clinical Stability

Abstract Background Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens. Omadacycline was recently approved in the United States for treatment of adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections. Analyses were undertaken to determine whether PORT risk class and CURB-65 score influence the pharmacokinetics of omadacycline in patients with CABP. Methods Omadacycline pharmacokinetic data were available from omadacycline-treated patients with CABP enrolled in the Phase 3 OPTIC Study. Patients received omadacycline 100 mg IV q12h on Day 1 followed by 100 mg IV q24h. After Day 3, patients could be switched to 300 mg PO q24h if predefined clinical stability criteria were met. Four pharmacokinetic samples per patient were collected between Days 2 and 5. These data were previously utilized in the development of a population pharmacokinetic model describing the disposition of omadacycline [Microbe 2018; Abstr SAT-628]. Individual post-hoc parameter estimates for patients enrolled in the OPTIC study were utilized to compute Day 1 total-drug plasma area under the concentration-time curve (AUC) values following administration of omadacycline 100 mg IV q12h. Differences among these AUC values by PORT risk class and CURB-65 score were assessed using a one-way ANOVA. Results A total of 187 pharmacokinetic samples were available from 50 patients. Among the patients classified as PORT risk class II, III, and IV (n = 12, 28, and 10, respectively), mean Day 1 omadacycline AUC values were 10.2, 11.0, and 12.0 mg L/h, respectively. Among patients with CURB-65 scores of 0, 1, and 2 (n = 23, 23, and 4, respectively), mean Day 1 omadacycline AUC values were 10.6, 11.6, and 9.7 mg L/h, respectively. The differences in mean AUC values were not statistically significant among patients by PORT risk class (P = 0.248) and CURB-65 score groups (P = 0.745). Moreover, variability was similar across these groups as displayed in Figure 1. Conclusion Omadacycline exposures were similar across PORT risk class and CURB-65 score groups; thus, omadacycline dose adjustments based on these classifications are likely not warranted. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Fekade B. Sime ◽  
Melissa Lassig-Smith ◽  
Therese Starr ◽  
Janine Stuart ◽  
Saurabh Pandey ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Rate Constant ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Peripheral Compartment ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Dosing Regimens

ABSTRACT Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean ± standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 ± 3.2 and 25.4 ± 9.4 liters/h, V of 20.4 ± 3.7 and 32.4 ± 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 ± 0.74 and 2.96 ± 8.6 h−1, and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 ± 0.37 and 26.5 ± 8.4 h−1. With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was ≥85% for directed therapy (MIC ≤ 4 mg/liter). However, for empirical coverage (MIC up to 64 mg/liter), the FTA was 84% with the 1.5-g q8h regimen when creatinine clearance is 180 ml/min/1.73 m2, whereas the 3.0-g q8h regimen consistently achieved an FTA of ≥85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT>MIC), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT>MIC is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.

scholarly journals Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

2013 ◽  
Vol 58 (1) ◽  
pp. 432-439 ◽  
Author(s):  
Brioni R. Moore ◽  
Sam Salman ◽  
John Benjamin ◽  
Madhu Page-Sharp ◽  
Leanne J. Robinson ◽  
...  
Keyword(s):  
Single Dose ◽  
Vivax Malaria ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Pharmacokinetic Data ◽  
Radical Cure ◽  
Papua New Guinean

ABSTRACTSince conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higherCmaxfor PMQ and CPMQ, respectively. All predicted medianCmaxconcentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group.

Quantitative Pharmacogenetics of Cyclophosphamide in Patients with Hematological Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4604-4604
Author(s):  
Moustapha Hassan ◽  
Hanjing Xie ◽  
Lars Ståhle ◽  
Zuzana Hassan ◽  
Eva Kimby
Keyword(s):  
Liver Function ◽  
Negative Correlation ◽  
Hematological Malignancies ◽  
Population Analysis ◽  
Plasma Concentrations ◽  
Significant Negative Correlation ◽  
Interindividual Variation ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
Treatment Data

Abstract A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, the pharmacokinetics of CPA and its active metabolite 4-OH-CPA were estimated in patients with hematological tumors and related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated. Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1 g/m²) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling. The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3- fold, respectively. A positive correlation was found between half-lives of CPA and 4-OH-CPA (p<0.05) and there was a significant negative correlation between AUCs of CPA and 4-OH-CPA. In the population analysis the clearance contribution of the CYP2B6 G516T variant allele was about twice the wild type gene while the genotype of CYP2C9 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation. There is a considerable variation in CPA formation of 4-OH-CPA among patients. The liver function influences CPA metabolism. Presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation, a substantial variation among patients remain to be explained.

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