Prediction of Plasma Concentration-time Profiles of Drugs in Humans from Animals Following Oral Administration: An Allometric Approach

2016 ◽  
Vol 17 (10) ◽  
pp. 1006-1013
Author(s):  
Iftekhar Mahmood
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Time Profiles ◽  
Concentration Time

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.

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.

Prediction of ACNU plasma concentration-time profiles in humans by animal scale-up

1990 ◽  
Vol 27 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Yoshihiro Mitsuhashi ◽  
Yuichi Sugiyama ◽  
Shogo Ozawa ◽  
Takashi Nitanai ◽  
Kunihiro Sasahara ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Scale Up ◽  
Time Profiles ◽  
Concentration Time

scholarly journals The Determination of 10 Compounds of GuiZhi Decoction in Rat Plasma after Oral Administration by HPLC-MS/MS and its Application to a Pharmacokinetic Study

2021 ◽  
Author(s):  
Huan Gao ◽  
Qin Guo ◽  
Lishi Zhang ◽  
Jiannan Song ◽  
Dong Bai ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Administration ◽  
Lower Limit ◽  
Intravenous Injection ◽  
Pharmacokinetic Study ◽  
Rat Plasma ◽  
Glycyrrhetinic Acid ◽  
Concentration Time ◽  
Guizhi Decoction

Abstract Background: Guizhi Decoction (GZD), a traditional Chinese medical formula, has been commonly used to treat fever, sweating, and cold in China. Methods: The high performance liquid chromatography -tandem mass spectrometry ( HPLC-MS/MS ) method was established for the determination of 10 compounds, including cinnamic acid , paeoniflorin, albiflorin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, glycyrrhetinic acid, and 6-gingerol. And the specificity, linearity, lower limit of quantification (LLOQ), lower limit of detection (LLOD), precision and accuracy, recovery, matrix effect, and stability were used to verify the HPLC-MS/MS method. This validated method was successfully applied for pharmacokinetic study of the 10 compounds in rat plasma after oral administration of GZD in three doses (40 g crude drug·kg −1 , 20 g crude drug·kg −1 , 10 g crude drug·kg −1 ) and intravenous injection of GZD extraction at a dose of 2.0 g crude drug·kg −1 .The measurements of pharmacokinetic parameters including AUC 0–∞ , T 1/2 , T max , C max , Vz_F, Cl_F, and MRT, were performed using a non-compartmental model with Winnonlin 8.1 software. Results: The results showed that 10 compounds were detected in plasma after oral administration of GZD. the compounds (except for glycyrrhetinic acid) reached the maximum blood concentration quickly, whose Tmax was about 0.1-0.2 min. And a total of 9 compounds were detected after intravenous injection of GZD. The plasma concentration-time curve of these compounds declines rapidly at the beginning, and then decreased slowly, indicating that the plasma concentration-time curves were double exponential function curves. Conclusions: In this study, the developed method was suitable for pharmacokinetic analysis of the main compounds of GZD in rat plasma, and may reveal the pharmacodynamic material basis of GZD and provide a reference for the rational use of GZD in the clinic.

A Phase I Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of the Hepcidin Antagonist PRS-080#022. Results from a Randomized, Placebo Controlled, Double-Blind Study Following Single Administration to Healthy Subjectsa

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 536-536 ◽  
Author(s):  
Ulrich Moebius ◽  
Werner Feuerer ◽  
Edgar Fenzl ◽  
Rachel van Swelm ◽  
Dorine W. Swinkels ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Plasma Concentration ◽  
Phase I Study ◽  
Serum Iron ◽  
Transferrin Saturation ◽  
Arithmetic Mean ◽  
Iron Availability ◽  
Double Blind ◽  
Time Profiles ◽  
Concentration Time

Abstract PRS-080#022 is a 20kD AnticalinTM protein linked to 30kD linear poly-ethylene-glycol that specifically binds to human hepcidin 25, thereby inhibiting its activity. PRS-080#022 is developed for the treatment of functional iron deficient anemia associated with chronic kidney disease or cancer. Elevated levels of hepcidin restrict iron availability and contribute to functional iron deficiency and anemia. Thus, antagonizing hepcidin with PRS-080#022 has the potential to improve iron availability and erythropoiesis, thereby avoiding overload with exogenous iron and reducing the administered levels of Erythropoiesis-Stimulating Agents. 48 healthy male subjects were treated in this placebo controlled, double-blind Phase I study with ascending doses of PRS-080#022 in 6 cohorts at 0.08, 0.4, 1.2, 4.0, 8.0, and 16.0 mg/kg. 6 subjects per cohort received PRS-080#022 and 2 subjects received placebo (NCT02340572). Placebo or active treatments were administered by intravenous infusion over 2 hours. Safety, tolerability, the pharmacokinetics of total and free PRS-080#022, serum hepcidin concentrations as well as parameters of iron metabolism (ferritin, serum iron, transferrin saturation, reticulocytes and hemoglobin) were investigated. PRS-080#022 was well tolerated. 39 adverse events (AE) were reported during or after treatment in 22 subjects. All such AEs were mild or moderate and no serious AE was observed. Headache was the most frequently observed AE (10 subjects). Otherwise, no association of AEs to specific organs and no apparent dose dependency or difference between placebo and active treatment were observed. Notably, no hypersensitivity or infusion reactions were noted and vital signs, body temperature and ECG were unchanged. Pharmocokinetics of total PRS-080#022 followed a two-compartment model and was consistent between dose cohorts and within subjects of each cohort (Figure 1). Maximal concentration (Cmax) and area under the time curve (AUC) increased proportionally with dose (Table 1). Cmax was reached about 1 h after the 2 h infusion period (Table 1). The terminal plasma half life (T1/2) of PRS-080#022 ranged from 71 to 81 hours among dose cohorts (Table 1). The volume of distribution was small with 49 to 65 ml/kg, consistent with a distribution mainly to the blood volume. Administration of PRS-080#022 resulted in a decrease of free hepcidin which was observed already 1 h after start of infusion. PRS-080#022 administration induced a transient increase in serum iron concentration and transferrin saturation (TSAT), with both responses exhibiting a comparable time course and at doses of 0.4 mg/kg and higher. TSAT increased to > 90% in individual subjects. Serum iron concentrations reached about 50 µmol/l in individual subjects and did not further increase with dose. Importantly, the time period at which elevated serum iron concentrations and TSAT were observed increased with dose from about 18 h at 0.4 mg/kg to about 120 h at 16 mg/kg PRS-080#022. This is reflected by an increase of the AUC of the serum iron response relative to baseline and placebo (Table 1). In contrast, ferritin levels were largely unaffected by treatment. The excellent safety profile and the confirmed activity of PRS-080#022 on iron metabolism observed in healthy subjects warrants further investigations in anemic patients. A study investigating safety, pharmacokinetics and activity on erythropoiesis in anemic end-stage chronic kidney disease patients is in preparation. aFunded by the European Community FP7 health program grant GA-No. 278408 and supported by the EUROCALIN consortium (www.eurocalin-fp7.eu) Table. Summary of pharmacokinetic and pharmacodynamic parameters PRS-080#022 dose[mg/kg] Pharmacokinetic Parameters (group means ± SD) Pharmacodynamic Parameter(group means ± SD) Cmax[µg/ml] AUC0-inf[h*µg/ml] Tmax[h] T1/2[h] Vss[ml/kg] Serum Iron AUC0-240# [h*µmol/l] 0.08 2.1±0.3 162 ± 17 2.8 ± 0.4 81.2 ± 8.7 56.2 ± 8.0 39 ± 2807 0.4 10.6 ± 1.6 761 ± 163 3.3 ± 1.6 70.5 ± 27.7 54.2 ± 9.8 1174 ± 1150 1.2 33.9 ± 4.4 2264 ±167 2.7 ± 0.8 80.0 ± 10.3 51.3 ± 4.1 958 ± 1178 4.0 120.4 ± 19.6 7491 ± 730 3.7 ± 3.1 73.1 ± 8.9 47.8 ± 5.6 1579 ± 2222 8.0 246.3 ± 56.8 15066 ± 2496 4.3 ± 2.8 79.6 ± 9.7 53.3 ± 9.3 1134 ± 2207 16.0 366.2 ± 40.9 25572 ± 4075 3.0 ± 0.6 80.2 ± 11.6 64.6 ± 14.6 3480 ± 2123 #Response as Area Under the Curve 0-240h over baseline, placebo subtracted Figure 1. Arithmetic mean plasma concentration time profiles of total PRS-080#022 Figure 1. Arithmetic mean plasma concentration time profiles of total PRS-080#022 Disclosures Moebius: Pieris Pharmaceuticals Inc.: Employment. Feuerer:Pieris Pharmaceuticals Inc.: Other: contracted clinical research. Fenzl:Pieris Pharmaceuticals Inc.: Other: contracted clinical research. van Swelm:PIERIS: Other: member of the EU FP7 Eurocalin consortium. Swinkels:PIERIS: Other: member of EU FP7 Eurocalin consortium. Hohlbaum:Pieris Pharmaceuticals Inc.: Employment.

Prediction of Human Oral Plasma Concentration-Time Profiles Using Preclinical Data

2011 ◽  
Vol 50 (8) ◽  
pp. 505-517 ◽  
Author(s):  
An Van den Bergh ◽  
Vikash Sinha ◽  
Ron Gilissen ◽  
Roel Straetemans ◽  
Koen Wuyts ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Preclinical Data ◽  
Time Profiles ◽  
Concentration Time

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 Pharmacokinetics of Itraconazole in Diabetic Rats

2009 ◽  
Vol 54 (2) ◽  
pp. 931-933 ◽  
Author(s):  
Unji Lee ◽  
Young H. Choi ◽  
So H. Kim ◽  
Byung K. Lee
Keyword(s):  
Diabetes Mellitus ◽  
Plasma Concentration ◽  
Oral Administration ◽  
Intrinsic Clearance ◽  
Diabetic Rats ◽  
Clearance Rates ◽  
Time Curve ◽  
Concentration Time ◽  
Streptozotocin Induced Diabetes ◽  
Plasma Concentration Time Curve

ABSTRACT After intravenous or oral administration of 10 mg/kg itraconazole to rats with streptozotocin-induced diabetes mellitus and to control rats, the total area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24) for itraconazole and that for its metabolite, 7-hydroxyitraconazole, were similar between the two groups of rats. This may be explained by the comparable hepatic and intestinal intrinsic clearance rates for the disappearance of itraconazole and the formation of 7-hydroxyitraconazole in both groups of rats.

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