scholarly journals The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19

2020 ◽  
Author(s):  
Virginia D. Schmith ◽  
Jie (Jessie) Zhou ◽  
Lauren RL Lohmer
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Maximum Plasma ◽  
Time Profiles ◽  
Concentration Time ◽  
Single Oral Administration ◽  
The Ideal

AbstractIntroductionCaly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC50, 2 µM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted.MethodSimulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose.ResultsPlasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC50 in lungs after single oral administration of the approved dose (predicted lung: 0.0857 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 µM).ConclusionsThe likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.

Evaluating the clinical impact of a shortened infusion duration for ramucirumab: A population pharmacokinetic model-based approach.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 191-191
Author(s):  
Paolo Abada ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Study Data ◽  
Population Pharmacokinetic ◽  
Time Profiles ◽  
Concentration Time ◽  
Increased Risk ◽  
Grade 3 ◽  
Infusion Duration

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.

scholarly journals Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

2012 ◽  
Vol 116 (5) ◽  
pp. 1124-1133 ◽  
Author(s):  
Bruce Hullett ◽  
Sam Salman ◽  
Sean J. O'Halloran ◽  
Deborah Peirce ◽  
Kylie Davies ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Pharmacokinetic Model ◽  
Inhibitory Concentration ◽  
Prediction Interval ◽  
Cyclooxygenase 2 ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

A Chinese Traditional Medicine, Sho-Saiko-To (Xiao-Chaihu-Tang), Reduces the Bioavailability of Tolbutamide after Oral Administration in Rats

1999 ◽  
Vol 27 (03n04) ◽  
pp. 355-363 ◽  
Author(s):  
Nobuhiro Nishimura ◽  
Kohji Naora ◽  
Hidenari Hirano ◽  
Kikuo Iwamoto
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Oral Bioavailability ◽  
Absorption Rate ◽  
Hepatic Metabolism ◽  
Chinese Traditional Medicine ◽  
Time Curve ◽  
Concentration Time ◽  
Single Oral Administration ◽  
Plasma Concentration Time Curve

The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were investigated in rats. After intravenous administration of tolbutamide (5 mg/kg), no significant change in the pharma-cokinetics of tolbutamide was observed in both groups of single and multiple (7 days) pre-administration of Sho-saiko-to (50 mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co-administration of Sho-saiko-to tended to accelerate the initial absorption rate of tolbutamide. The area under the plasma concentration-time curve of tolbutamide after oral administration was significantly reduced by Sho-saiko-to. Subsequently, a significant decrease was observed in the oral bioavailability of this drug when Sho-saiko-to was given concomitantly. These findings suggest that Sho-saiko-to reduces the bioavailability of tolbutamide after oral dministration in rats, and that this change is not related to hepatic metabolism.

scholarly journals Bioequivalence Study of Two Formulations of Tramadol Capsules in Healthy Myanmar Volunteers

2020 ◽  
Author(s):  
Ye Htut Linn ◽  
Myat Myat Soe ◽  
K Khine Thu ◽  
Thida Tun ◽  
Mi Kun Kaw San ◽  
...  
Keyword(s):  
Oral Administration ◽  
Generic Drugs ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Time Data ◽  
Fluorescence Detector ◽  
Fasting Condition ◽  
Concentration Time ◽  
Single Oral Administration

Background: Tramadol is one of the most commonly used analgesics, thanks to its efficacy and safety. It is widely used in Myanmar for postoperative and cancer pain control. The use of generic drugs has been steadily increasing worldwide, mostly in developing countries. Generic drugs should have efficacy and safety comparable to their innovators or other approved generic products. Objectives: This study aims to compare the bioequivalence of locally producing, Tramadol BPI® capsule (test product) with the Tramazac® capsule (reference product) in healthy Myanmar volunteers. Methods: The bioequivalence was determined in 16 healthy Myanmar volunteers after a single oral administration of 100 mg tramadol (under fasting condition) in a randomized, openlabel, two-period, and two-treatment crossover study with a two-week washout period. Blood samples were collected at specified times, and plasma tramadol concentrations were measured with a validated high-performance liquid chromatography method with a fluorescence detector. Pharmacokinetic parameters were determined using the plasma concentration-time data in a noncompartmental model. Results: The analysis of variance of the logarithmically transformed parameters (maximum plasma concentration (Cmax), Area Under the concentration-time Curve from the time of administration to the last measured concentration (AUC0-t), and to infinity (AUC0-∞) revealed no sequence, period, and formulation effects between the test and reference products. Significant differences were found between the subjects within the sequence for both AUC0-t, and AUC0-∞, indicating a substantial intersubject variation. The geometric mean ratio of test/reference and their 90% confidence intervals were within the ASEAN (Association of Southeast Asian Nations) bioequivalence acceptance interval of 80% to 125%. Conclusion: Tramadol BPI® and Tramazac® capsules, after a single oral administration of 100 mg, were bioequivalent in respect of their rate and extent of absorption under fasting condition.

scholarly journals Pharmacokinetics and skin concentrations of lincomycin after intravenous and oral administration to cats

2013 ◽  
Vol 84 (1) ◽  
Author(s):  
Gabriela A. Albarellos ◽  
Laura Montoya ◽  
Graciela A.A. Denamiel ◽  
Sabrina M. Passini ◽  
María F. Landoni
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Half Life ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma ◽  
Elimination Half Life ◽  
Concentration Time ◽  
Elimination Half ◽  
Intravenous And Oral Administration

The aim of the present study was to describe the plasma pharmacokinetic profile and skin concentrations of lincomycin after intravenous administration of a 15% solution and oral administration of 300 mg tablets at a dosing rate of 15 mg/kg to cats. Susceptibility of staphylococci (n = 31) and streptococci (n = 23) strains isolated from clinical cases was also determined. Lincomycin plasma and skin concentrations were determined by microbiological assay using Kocuria rhizophila ATCC 9341 as test microorganism. Susceptibility was established by the antimicrobial disc diffusion test. Individual lincomycin plasma concentration–time curves were analysed by a non-compartmental approach. After intravenous administration, volume of distribution, body clearance and elimination half-life were 0.97 L/kg ± 0.15 L/kg, 0.17 L/kg ± 0.06 L/h.kg and 4.20 h ± 1.12 h, respectively. After oral administration, peak plasma concentration, time of maximum plasma concentration and bioavailability were 22.52 µg/mL ± 10.97 µg/mL, 0.80 h ± 0.11 h and 81.78% ± 24.05%, respectively. Two hours after lincomycin administration, skin concentrations were 17.26 µg/mL ± 1.32 µg/mL (intravenous) and 16.58 µg/mL ± 0.90 µg/mL (oral). The corresponding skin: plasma ratios were 2.08 ± 0.47 (intravenous) and 1.84 ± 0.97 (oral). The majority of staphylococci and streptococci tested in this study were susceptible to lincosamides (87.09% and 69.56%, respectively). In conclusion, lincomycin administered orally at the assayed dose showed a good pharmacokinetic profile, with a long elimination half-life and effective skin concentration. Therefore, it could be a good first option for treating skin infections in cats.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

scholarly journals Plasma profile of cimicoxib in sheep after oral administration at two different rates

2017 ◽  
Vol 20 (3) ◽  
pp. 535-538
Author(s):  
A. Di Salvo ◽  
M. Giorgi ◽  
H.K. Lee ◽  
C. Vercelli ◽  
F. Rueca ◽  
...  
Keyword(s):  
Oral Administration ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Individual Variability ◽  
Maximum Plasma ◽  
Dose Rates ◽  
Single Oral Administration ◽  
Concentration Peak ◽  
Value Range ◽  
Slow Absorption

Abstract Sheep are often subjected to painful procedures and thus they need to be treated with analgesics. Nevertheless, knowledges about pharmacokinetic features of these drugs in this species are poor. The aim of this study was to evaluate plasma behaviour of cimicoxib in sheep after a single oral administration at two different dose rates (4 and 6 mg/kg). Maximum plasma concentrations of cimicoxib were equal to 273.78 (median value; range 189.00-567.32) and 565.01 (range 308.27-822.59) ng/mL after treatment with 4 and 6 mg/kg, respectively. The time of maximum concentration (Tmax) was achieved between 4 and 10 hours following treatment at the lower dose, and between 6 and 10 hours after the administration of the higher dose, with one sheep achieving the concentration peak at 0.75 hours. The slow absorption and the great individual variability in plasma concentration, probably due to ruminal effects, suggest that cimicoxib is not suitable for oral treatment in sheep.

scholarly journals Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 113 ◽  
Author(s):  
Noriyuki Ishihara ◽  
Nobuhiro Nishimura ◽  
Kazuro Ikawa ◽  
Fumi Karino ◽  
Kiyotaka Miura ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Elderly Patients ◽  
Distribution Volume ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Target Attainment ◽  
Old Patients ◽  
Final Model ◽  
Concentration Time ◽  
Population Pk

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

scholarly journals Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution

Pharmaceutics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 251 ◽  
Author(s):  
Tae Hwan Kim ◽  
Soyoung Shin ◽  
Seok Won Jeong ◽  
Jong Bong Lee ◽  
Beom Soo Shin
Keyword(s):  
Dissolution Kinetics ◽  
Immediate Release ◽  
Relative Bioavailability ◽  
Wet Granulation ◽  
Population Pharmacokinetic ◽  
Beagle Dogs ◽  
Concentration Time ◽  
In Vivo Dissolution

This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.

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