scholarly journals Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial

2020 ◽  
Vol 75 (4) ◽  
pp. 1014-1018
Author(s):  
Benoit Guery ◽  
Areti Georgopali ◽  
Andreas Karas ◽  
Gbenga Kazeem ◽  
Ingrid Michon ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Analysis ◽  
Plasma Samples ◽  
Post Dose ◽  
Recommended Treatment ◽  
Clostridioides Difficile ◽  
Stool Samples

Abstract Background Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown. Objectives To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI. Methods In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1–5; once daily on alternate days, Days 7–25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1. Results Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ± 1 and Day 25/26 were 0.0252 (0.0038–0.1220) mg/L and 0.0069 (0–0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142–0.3250) mg/L and 0.0206 (0–0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ± 1 were 272.5 (0–524) mg/kg and 280.5 (0–1120) mg/kg, respectively. Conclusions EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.

scholarly journals Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Cholic Acid (MT921) after a Subcutaneous Injection in the Submental Area to Humans

2021 ◽  
Vol 14 (8) ◽  
pp. 830
Author(s):  
Hyewon Chung ◽  
Jin-Woo Park ◽  
Dai-Hyun Kim ◽  
Soo-Hong Seo ◽  
Kyoung-Ah Kim ◽  
...  
Keyword(s):  
Cholic Acid ◽  
Deoxycholic Acid ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Systemic Exposure ◽  
Blood Lipid ◽  
Pharmacokinetic Analysis ◽  
Post Dose ◽  
Before And After

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, 120 mg, and 150 mg) of MT921. Blood samples were obtained for a 24-h period before and after injecting MT921 to the submental fat area. Plasma concentrations of cholic acid and deoxycholic acid were determined for pharmacokinetic analysis. Levels of free fatty acid, triglyceride, and total cholesterol were measured for pharmacodynamic analysis. Safety and tolerability were assessed until 21 days post-dose. While systemic exposure to cholic acid tended to increase as the MT921 dose increased, pharmacokinetic profiles of deoxycholic acid were similar among dose groups without showing significant changes. Pharmacodynamic profiles were comparable when measured at baseline and post-dose. The most frequent adverse events were injection site pain and edema. All adverse drug reactions resolved without treatment. MT921 appeared to be well-tolerated after an injection to the submental area at a dose up to 150 mg. Systemic exposure to cholic acid increased as the dose increased. Blood lipid profiles and deoxycholic acid levels were not affected by MT921 treatment.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Comparison of pharmacokinetics of omega-3 fatty acid supplements in monoacylglycerol or ethyl ester in humans: a randomized controlled trial

2020 ◽  
Author(s):  
Laurie Chevalier ◽  
Mélanie Plourde
Keyword(s):  
Plasma Concentration ◽  
Ethyl Ester ◽  
Controlled Trial ◽  
Plasma Concentrations ◽  
Controlled Clinical Trial ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Post Dose ◽  
Double Blind ◽  
Omega 3 Fatty Acid

Abstract Background A diet low in omega-3 fatty acids (n-3 FA) results in low plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main long chain n-3 FA. n-3 FA supplements on the market are esterified in triglycerides (TG) or ethyl ester (EE); the latter is absorbed less than other esterification forms. The objective of this study was to test and compare the pharmacokinetics of n-3 FA esterified in monoacylglycerides (MAG), a predigested form, with the EE form. Methods This study was a randomized, double-blind, crossover, controlled, clinical trial. Ten men and ten women between 18 and 60 years old were recruited. Participants received a single oral dose of 3 g of n-3 FA esterified in EE or MAG. Eleven blood samples were collected over 24 h post-dose. Plasma total lipids were extracted, methylated, and analyzed using gas chromatography. Results After receiving the MAG form, plasma EPA and DHA peaked at a concentration 3 and 2.5 times higher, respectively, than with the EE form. When provided in MAG form, n-3 FA plasma concentration during the absorption phase was on average 3–5 times higher than in EE form. When n-3 FAs were provided esterified in MAG, their concentration 24 h post-dose was higher than in EE. Males had a lower n-3 FA plasma concentration than females when n-3 FAs were provided in EE but there was no sexe difference when provided in MAG. Conclusions Plasma concentration of DHA and EPA was higher when provided in MAG than EE form.

Optimization of high-dose busulfan dosing in bone marrow transplant patients

1996 ◽  
Vol 2 (1_suppl) ◽  
pp. 18-26
Author(s):  
James S. Partyka ◽  
Cheryl Tate
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplant ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Marrow Transplant ◽  
High Dose ◽  
Medline Search ◽  
Transplant Patients

Objective. To review the pharmacokinetics profile of (HD-BU) high-dose busulfan, review published phar macodynamic relationships of high-dose busulfan and discuss clinical considerations of monitoring patients receiving high-dose busulfan. Data Sources. A MEDLINE search of articles published from 1985 to 1996 and a Cancerlit search of articles published from 1988 to 1996, using the Mesh headings "Busulfan (subheading: pharmacokinetics)," "Bone Marrow Transplantation" and "Hepatic Veno occlusive Disease." Study Selection. All human trials evaluating the pharmacokinetic profile and the pharmacodynamic relationships of high-dose busulfan in bone marrow transplant patients. Data Synthesis. Busulfan disposition has been extensively studied in both children and adults receiv ing high doses followed by stem cell rescue. Sample sizes ranged from 7 to 28 patients, with patients ranging from 0.3 to 60 years of age. Busulfan total doses ranged from 14 mg/kg to 640 mg/m2. A large interpatient variability has been reported in busulfan pharmacokinetics parameters for both children and adults. In adults, the maximum concentration (Cmax) achieved after the first oral dose of HD-BU ranged from 249 to 1512 ng/mL, the apparent volume of distribution (Vd) ranged from 0.56 to 0.66 L/kg, the total plasma clearance (CL) of busulfan ranged from 2.49 to 3.26 mL/min/kg, and the area under the time versus concentration curve (AUC) ranged from 103 to 21,120 ng h/mL. In children, the Cmax ranged from 577 to 1258 ng/mL, the Vd ranged from 0.74 to 1.42 L/kg, the CL of busulfan ranged from 3.26 to 8.91 mL/min/kg, and the AUC ranged from 309 to 13,129 ng h/mL. Several investigators have reported in creased busulfan CL, larger Vd and lower Cmax in children as compared to adults. In addition, children have lower AUCs as compared with adults when administered a fixed busulfan dose based on body weight. Lower busulfan AUCs in children appear to be the result of an increased systemic clearance and a larger volume of distribution as compared to adults. In adults, HD-BU systemic exposure have been corre lated to efficacy and toxicity in some studies; no prospective studies in children have established a clear role for routinely monitoring busulfan concen trations. Conclusions. Although routine monitoring with dosage adjustment of busulfan is probably warranted in some patients with extremely high or low busulfan plasma concentrations, clinical studies should con tinue to further define a therapeutic range for HD-BU.

scholarly journals Plasma oxylipins respond in a linear dose-response manner with increased intake of EPA and DHA: results from a randomized controlled trial in healthy humans

2019 ◽  
Vol 109 (5) ◽  
pp. 1251-1263 ◽  
Author(s):  
Annika I Ostermann ◽  
Annette L West ◽  
Kirsten Schoenfeld ◽  
Lucy M Browning ◽  
Celia G Walker ◽  
...  
Keyword(s):  
Dose Response ◽  
Controlled Trial ◽  
Plasma Concentrations ◽  
Blood Lipid ◽  
Linear Increase ◽  
Biologically Active ◽  
Plasma Samples ◽  
Omega 3 ◽  
Healthy Humans ◽  
Epa And Dha

ABSTRACT Background The health effects of long-chain omega-3 polyunsaturated fatty acids (n–3 PUFAs) are partly mediated by their oxidized metabolites, i.e., eicosanoids and other oxylipins. Some intervention studies have demonstrated that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase systemic concentrations of n–3 PUFA–derived oxylipins and moderately decrease arachidonic acid–derived oxylipins. There is no information on the dose-response of oxylipin concentrations after n–3 PUFA intake. Objective The aim of this study was to quantify oxylipins in human plasma samples from an intervention study in which participants were randomly assigned to different daily intakes of EPA and DHA for 12 mo. Methods Healthy adult men and women with low habitual fish consumption (n = 121) were randomly assigned to receive capsules providing doses of n–3 PUFAs reflecting 3 patterns of consumption of oily fish [1, 2, or 4 portions/wk with 3.27 g EPA + DHA (1:1.2, wt:wt) per portion] or placebo. Oxylipins were quantified in plasma after 3 and 12 mo. Relative and absolute changes of individual oxylipins were calculated and concentrations were correlated with the dose and the content of EPA and DHA in blood lipid pools. Results Seventy-three oxylipins, mostly hydroxy-, dihydroxy-, and epoxy-PUFAs, were quantified in the plasma samples. After 3 and 12 mo a linear increase with dose was observed for all EPA- and DHA-derived oxylipins. Cytochrome-P450-derived anti-inflammatory and cardioprotective epoxy-PUFAs increased linearly with n–3 PUFA dose and showed low interindividual variance (r2 > 0.95). Similarly, 5, 12-, and 15-lipoxygenase–derived hydroxy-PUFAs as well as those formed autoxidatively increased linearly. These include the precursors of so-called specialized pro-resolving lipid mediators (SPMs), e.g., 17-hydroxy-DHA and 18-hydroxy-EPA. Conclusions Plasma concentrations of biologically active oxylipins derived from n–3 PUFAs, including epoxy-PUFAs and SPM-precursors, increase linearly with elevated intake of EPA and DHA. Interindividual differences in resulting plasma concentrations are low. This trial was registered at controlled-trials.com as ISRCTN48398526.

scholarly journals Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

2018 ◽  
Vol 2 ◽  
pp. 239784731880115
Author(s):  
Derek E Murrell ◽  
Jessica M Coleman ◽  
Stacy D Brown ◽  
Sam Harirforoosh
Keyword(s):  
Plasma Concentration ◽  
Glycolic Acid ◽  
Kidney Injury ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Analysis ◽  
In Vivo Evaluation ◽  
Post Dose ◽  
Time Curve ◽  
Urinary Potassium

Aliskiren (ALS) is a direct renin inhibitor with low bioavailability and high drug cost. The goal of this study was to increase the bioavailability of ALS through nanoformulation. The optimized formulation was then evaluated in spontaneously hypertensive rats (SHRs). We developed an ALS poly(lactic- co-glycolic) acid nanoparticle (ALS-NP) through the emulsion–diffusion–evaporation method with various solvents, stabilizer concentrations, and centrifugation speeds. SHRs were orally dosed with 30 mg/kg ALS or dose equivalent ALS-NP. Several parameters were assayed in plasma and/or urine at baseline and 24 h post-dose, while pharmacokinetic analysis included serial sampling. The optimum formulation was found with ethyl acetate, a 1.00% w/v didodecyldimethylammonium bromide concentration, and a 10,000 r/min (15,554 g) centrifugation speed. A 168% relative bioavailability was observed as a result of ALS-NP administration along with significant, as determined by Student’s t-test, increases in the maximum ALS plasma concentration ( p = 0.0189) and the area under the plasma concentration–time curve from 0 to infinity ( p = 0.0095). Conversely, a reduction was found in oral volume of distribution ( p = 0.0009) and oral clearance ( p = 0.0298). Blood urea nitrogen increased significantly after dosing in both groups ( p < 0.0001 and p < 0.0001); however, no statistical difference was found between endpoint levels ( p > 0.05) following one-way analysis of variance (ANOVA). Kidney injury molecule-1 increased following ALS dosing ( p = 0.0486), while ALS-NP showed a decrease ( p = 0.027) which was also significantly decreased compared to ALS-Final ( p = 0.0008) when examined using two-way ANOVA. Urinary potassium excretion decreased significantly, as shown by two-way ANOVA, only in the ALS group ( p = 0.0274) which was also significantly reduced compared to ALS-NP-Final ( p = 0.016). Using the current formulation and at the dosage tested, ALS-NP showed a more favorable pharmacokinetic profile and positive kidney changes compared to ALS in regard to select outcomes. Thus, NP formulation may further improve ALS renoprotection in addition to increasing bioavailabilty.

scholarly journals Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Davis ◽  
Krishanu Sengupta ◽  
Venkata Krishnaraju Alluri ◽  
Trimurtulu Golakoti
Keyword(s):  
Plasma Concentrations ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Oral Ingestion ◽  
Post Dose ◽  
Geometric Means ◽  
Funding Sources ◽  
Healthy Humans

Abstract Objectives A randomized, open label, balanced, two-way crossover study compared the oral bioavailability and pharmacokinetic profiles of two Boswellia products standardized to 3-O-acetyl-11-Keto-β-boswellic acid (AKBA). Methods Twenty-two fasted male participants completed the study. They received a single oral-dose of water-soluble Boswellia extract 78% (LI51202F1) or the standard Boswellia extract 30% (5-Loxin) at 30 mg AKBA equivalent with 240 mL water on 2 separate occasions 12 days apart. Plasma AKBA and KBA were analyzed using a LC-MS/MS in pre- (0 hr) and post-dose (00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 04.00, 08.00, 12.00 and 24.00 hrs) blood samples. Pharmacokinetic analysis was performed using WinNonlin® version 7.0 (Pharsight corporation, USA). Results Comparative analysis of the pharmacokinetic parameters showed LI51202F1 had higher (111.11%) Cmax for AKBA vs. 5-Loxin. The bioavailability indicated by Geometric means of AUC0-t and AUC0-∞ were 25.49% and 16.13% higher in LI51202F1 than 5-Loxin. Conclusions The present study demonstrates that oral ingestion of water soluble and standard Boswellia extracts resulted in similar bioavailability. Interestingly, the water-soluble version exhibited higher Cmax and AUC values, which could be attributed to the improved solubility of LI51202F1. Funding Sources Laila Nutraceuticals.

scholarly journals Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

2016 ◽  
Vol 60 (3) ◽  
pp. 1830-1833 ◽  
Author(s):  
R. Brigg Turner ◽  
Aaron Cumpston ◽  
Michael Sweet ◽  
Frank Briggs ◽  
Douglas Slain ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Ideal Body Weight ◽  
Normal Weight ◽  
Controlled Study ◽  
Pharmacokinetic Analysis ◽  
Obese Patients ◽  
Time Curve

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m2, respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h;P= 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter;P= 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter;P= 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)

scholarly journals 701. An Open-label Phase 2a Study of Ibezapolstat, a Unique Gram-positive Selective Spectrum (GPSS) Antibiotic, for Patients with Clostridioides difficile Infection

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S451-S451
Author(s):  
Kevin W Garey ◽  
Khurshida Begum ◽  
Chenlin Hu ◽  
Weiqun Wang ◽  
Chris Lancaster ◽  
...  
Keyword(s):  
Clinical Cure ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Clinical Development ◽  
Open Label ◽  
Gram Positive ◽  
Clostridioides Difficile ◽  
Open Label Phase ◽  
Clostridioides Difficile Infection ◽  
Stool Samples

Abstract Background Ibezapolstat, a DNA polymerase IIIC inhibitor, currently in Phase 2 clinical development for treatment of C. difficile infection (CDI). Its unique mechanism of action targets low G+C content Gram-positive bacteria primarily Firmicutes including C. difficile. Phase I healthy volunteer results demonstrated a favorable microbiome profile suggestive of an anti-recurrence effect. The purpose of this study was to report clinical outcomes, pharmacokinetics, and microbiome changes from this Phase 2a clinical study and to continue to test for anti-recurrence microbiome properties. Methods Ibezapolstat 450 mg was given twice daily for 10 days to patients with mild-moderate CDI defined as diarrhea plus a positive C. difficile toxin test. Test of cure was evaluated at day 12 and sustained clinical cure at day 38. Stool samples were evaluated for C. difficile cultures and microbiome changes. Results Ten subjects (female: 50%) aged 50 ±15 years were enrolled. All ten subjects experienced a clinical cure by the test of cure visit at day 12 and all 10 subjects experienced a sustained clinical cure at the day 38 visit. Ibezapolstat was well tolerated with 1 adverse event (nausea) probably related to drug. Ibezapolstat systemic exposure was minimal with no plasma level reaching 1 ug/mL any time during therapy. Ibezapolstat colonic concentrations averaged 400 ug/g stool at day 3 and greater than 1,000 ug/g by day 10 of dosing. Six of the seven available baseline stool samples grew toxigenic C. difficile of various ribotypes including RT078-226 and RT014-020 (Ibezapolstat MIC range: 0.25-1 ug/mL). Follow-up cultures were no growth starting from day 3 stool cultures. Microbiome changes included overgrowth of Actinobacteria and/or Firmicute phylum species while on therapy. Conclusion Favorable clinical efficacy and safety results were observed in ibezapolstat patients with CDI including 100% clinical cure and sustained clinical cure. These results begin to validate our approach to ibezapolstat development in that the favorable microbiome effects seen in healthy Phase 1 volunteers may be predictive of beneficial patient outcomes, including low rates of recurrence. These results support the continued clinical development of ibezapolstat. Disclosures Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support) Michael Silverman, MD, Acurx Pharmaceuticals (Consultant)

Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine

2020 ◽  
Vol 17 (3) ◽  
pp. 387-396 ◽  
Author(s):  
Kushal Shah ◽  
Briann Fischetti ◽  
Agnes Cha ◽  
David R. Taft
Keyword(s):  
Renal Impairment ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Transcriptase Inhibitor ◽  
Pbpk Modeling ◽  
Published Data ◽  
Post Dose ◽  
Model Simulations ◽  
The Impact

Background: Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE. Objective: To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator. Methods: The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment. Results: Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme. Conclusion: This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.

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