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.

scholarly journals Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Wendy Ankrom ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Adedayo Adedoyin ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Transcriptase Inhibitor ◽  
Maximum Plasma ◽  
Minor Effect ◽  
Minimal Impact

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0–∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.)

scholarly journals Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

2021 ◽  
Author(s):  
Naveed Shaik ◽  
Robert R. LaBadie ◽  
Brian Hee ◽  
Geoffrey Chan
Keyword(s):  
Plasma Concentration ◽  
Renal Impairment ◽  
Peak Plasma ◽  
Severe Renal Impairment ◽  
Peak Plasma Concentration ◽  
Safety Data ◽  
Normal Group ◽  
Open Label ◽  
Post Dose ◽  
The Impact

Abstract Purpose Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. Methods Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. Results All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142–295%) and 137% (97–193%) in the moderate group, and 202% (146–281%) and 120% (77–188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. Conclusion The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. Trial registration: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

scholarly journals Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis

2021 ◽  
Vol 26 (8) ◽  
pp. 809-814
Author(s):  
Stephen J. Balevic ◽  
Mara L. Becker ◽  
Daniel Gonzalez ◽  
Ryan S. Funk
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Body Size ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Standard Of Care ◽  
Continuous Measure ◽  
Cross Sectional ◽  
Cdc Guidelines ◽  
Dosing Strategies ◽  
The Impact

OBJECTIVE To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). METHODS We conducted a pilot, cross-sectional, observational study in a real-world cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage. Body size was analyzed as a continuous measure using weight and body mass index (BMI) percentiles and categorically using BMI percentile classifications according to the CDC guidelines. RESULTS We enrolled a total of 29 children. Each child provided one plasma sample for ETN concentration measurement, and all participants were receiving subcutaneous ETN dosed weekly. We observed that the ETN concentration normalized for dose decreased significantly as a function of weight (p = 0.004) and BMI percentile (p = 0.04). Similarly, we observed a progressive decline in mean and median dose-normalized concentrations across higher body size categories. Because of reaching maximum ETN dosage (50 mg), 7 of 8 children (87.5%) with obesity received a weight-based dosage &lt; 0.8 mg/kg/dose. CONCLUSIONS We found that higher body weight and BMI percentile are significantly and negatively associated with ETN drug serum concentration, accounting for differences in dosing. Our data suggest that children who are obese may be routinely under-dosed using current dosing strategies. Inadequate dosing may increase the risk for therapeutic failure and long-term morbidity in a developing child. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

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.

scholarly journals P52 Low and erratic exposure of oral acetaminophen in critically ill children determined with a 14C microtracer study: a case for IV acetaminophen for acute pain management?

2019 ◽  
Vol 104 (6) ◽  
pp. e38.2-e39
Author(s):  
N Kleiber ◽  
E Calvier ◽  
MG Mooij ◽  
EHJ Krekels ◽  
WH Vaes ◽  
...  
Keyword(s):  
Pain Management ◽  
Acute Pain ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Critically Ill Children ◽  
Acute Pain Management ◽  
Post Dose ◽  
Population Pk ◽  
Pediatric Icu ◽  
Oral Doses

BackgroundDespite being the most commonly used analgesic and antipyretic, oral APAP bioavailability has not been determined in children. The aim of this study is to compare exposure after oral vs iv APAP using the PK data of the first pediatric oral bioavailability 14C microtracer study.MethodsDesignbioavailability microtracer population PK studyParticipantspatients < 6 yrs old in the pediatric ICU who received 15 mg/kg iv APAP q6hInterventiona single microdose of 14CAPAP (3µg/kg) given orally at the same time as a therapeutic iv doseData collectionBlood was sampled 8 times up to 24 h post-doseData analysispopulation PK analysis using NONMEM. Based on the model, exposure after oral vs iv was compared by simulating the concentration-time profiles and Css (targeted: 10 mg/L ± 20% deviation).3 doses were simulated: 15 mg/kg q6h oral and iv and 22.5 mg/kg oral q6h. 1000 simulations were performed and the percentage of patients reaching the targeted mean Css of 10 mg/L±20% were compared.ResultsOral bioavailibity was 72% (range:11–91%). After 15 mg/kg APAP, the median simulated oral Css was subtherapeutic (6.5 mg/L), but therapeutic (10 mg/L) for IV dosing (15 mg/kg). Patients were 2.5 times less likely to reach therapeutic plasma concentrations with 15 mg/kg oral vs iv APAP.With the maximal recommended oral doses of 22.5 mg/kg 6 h aimed to overcome the 72% bioavailability, median mean Css were therapeutic but overexposure and underexposure were more common than with iv (37 vs 32% Css< 8 mg/L and 30 vs 21% Css>12 mg/L).ConclusionCompared to IV, the usual (15 mg/kg) oral APAP doses result in low systemic exposure with subsequent risk of therapeutic failure. When oral doses are increased to overcome the low bioavailability, underdosing still occurs and overdosing was observed in patients with high bioavailability. IV APAP should therefore be preferred for acute pain management.Disclosure(s)Nothing to disclose

scholarly journals Pharmacokinetic Assessment of Nevirapine and Metabolites in Human Immunodeficiency Virus Type 1-Infected Patients with Hepatic Fibrosis

2009 ◽  
Vol 53 (10) ◽  
pp. 4147-4152 ◽  
Author(s):  
Anna Maria Cammett ◽  
Thomas R. MacGregor ◽  
Jan M. Wruck ◽  
Franco Felizarta ◽  
Patrick Miailhes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Liver Disease ◽  
Hepatic Fibrosis ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Transcriptase Inhibitor ◽  
Multiple Dosing ◽  
Immunodeficiency Virus ◽  
Group 2 ◽  
Group 1

ABSTRACT Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for ≥6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

scholarly journals Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers

2016 ◽  
Vol 19 (2) ◽  
pp. 198 ◽  
Author(s):  
Ioana Todor ◽  
Adina Popa ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Cyp2d6 Activity ◽  
The Mean ◽  
The Impact ◽  
Pharmacokinetic Drug

Purpose: To evaluate the impact of bupropion on the pharmacokinetic profile of atomoxetine and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide, in healthy volunteers. Methods: An open-label, non-randomized, two-period, sequential clinical trial was conducted as follows: during Period I (Reference), each volunteer received a single oral dose of 25 mg atomoxetine, whilst during Period II (Test), a combination of 25 mg atomoxetine and 300 mg bupropion was administered to all volunteers, after a pretreatment regimen with bupropion for 7 days. Next, after determining atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations, their pharmacokinetic parameters were calculated using a noncompartmental method and subsequently compared to determine any statistically significant differences between the two periods. Results: Bupropion intake influenced all the pharmacokinetic parameters of both atomoxetine and its metabolite. For atomoxetine, Cmax increased from 226±96.1 to 386±137 ng/mL and more importantly, AUC0-∞ was significantly increasedfrom 1580±1040 to 8060±4160 ng*h/mL, while the mean t1/2 was prolonged after bupropion pretreatment. For 4-hydroxyatomoxetine-O-glucuronide, Cmax and AUC0-∞  were decreased from 707±269 to 212±145 ng/mL and from 5750±1240 to 3860±1220 ng*h/mL, respectively. Conclusions: These results demonstrated that the effect of bupropion on CYP2D6 activity was responsible for an increased systemic exposure to atomoxetine (5.1-fold) and also for a decreased exposure to its main metabolite (1.5-fold). Additional studies are required in order to evaluate the clinical relevance of this pharmacokinetic drug interaction.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 105 ◽  
Author(s):  
Kristin Follman ◽  
Marilyn Morris
Keyword(s):  
Renal Impairment ◽  
A Priori ◽  
Pbpk Modeling ◽  
Physiologically Based Pharmacokinetic ◽  
Simulation Based ◽  
Prevalent Disease ◽  
Expression Activity ◽  
The Impact

Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define the impact of these factors in PK in RI for a model substrate, nifedipine. Changes in fraction unbound and DME expression/activity had profound effects on PK in RI. Increasing fraction unbound and DME expression resulted in a reduction in exposure of nifedipine, while the reduction of DME activity resulted in an increase in exposure. In vitro and preclinical data were utilized to inform simulations for nifedipine, sildenafil and zidovudine. Increasing fraction unbound and changes in the expression/activity of DMEs led to improved predictions of PK. Further characterization of the impact of RI on these factors is warranted in order to better inform a priori predictions of PK in RI.

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 P332 Population pharmacokinetics of ozanimod and active metabolite CC112273 in patients with ulcerative colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S355-S357
Author(s):  
J Shen ◽  
D Tatosian ◽  
L Sid-Otmane ◽  
N Teuscher ◽  
L Chen ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Body Weight ◽  
Drug Exposure ◽  
Smoking Status ◽  
Plasma Concentrations ◽  
Hepatic Function ◽  
Population Pk ◽  
Apparent Clearance ◽  
Post Hoc ◽  
The Impact

Abstract Background Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and under development for ulcerative colitis (UC) and Crohn’s disease (CD). Following multiple dosing of ozanimod in healthy subjects, ozanimod and two of the active metabolites CC112273 and CC1084037 represent approximately 6%, 73%, and 15% of circulating total active drug exposure, respectively. Two separate pharmacokinetic (PK) models were developed for the most prominent metabolite CC112273 and ozanimod. CC1084037 was not modeled due to the high correlation between CC112273 and CC1084037 plasma concentrations. Therefore, this analysis aims to characterise the PK of ozanimod and the major metabolite CC112273 in UC and RMS population. Methods Subjects from 11 studies (Phase 1 to Phase 3) in healthy volunteers, RMS, and UC patients were included in this population PK analysis. The analyses included a total of 18901 concentrations from 2890 subjects for CC112273 and 18834 PK concentrations from 2977 subjects for ozanimod. A 2-compartment model was used to describe the concentration-time profiles of both ozanimod and CC112273, separately. The influence of weight, age, sex, race, disease, or smoking status and hepatic function on the PK of ozanimod and CC112273 were explored. The impact of concomitant corticosteroids on CC112273 PK were evaluated post hoc. Results While the overall apparent clearance of ozanimod was 7% lower in RMS patients compared to UC, similar exposures were observed in both populations. The most influential covariate on ozanimod PK was body weight, with a modest 23% increase in apparent clearance for a 102-kg subject relative to a 70-kg subject (Figure 1). The apparent clearance of CC112273 was 16% greater in RMS patients compared to UC patients, resulting in a slightly higher exposure for UC patients. Increasing body weight had a modest reduction in clearance, while smoking had the largest influence on CC112273 PK of approximately 108% increased clearance (Figure 2). Post-hoc results showed no impact of concomitant prednisone or prednisolone on the PK of CC112273. Other factors, including age, race, sex, or hepatic impairment did not impact the PK of ozanimod or CC112273 PK. Conclusion The population PK model of CC112273 indicates that covariates with the largest effect on CC112273 PK parameters were body weight and smoking status. However, no covariate impacted clearance by more than 25%. The PK of ozanimod and CC112273 were not meaningfully impacted by age including in the elderly, body weight, race, sex, hepatic function, or concomitant prednisone or prednisolone. Overall, the PK of ozanimod and CC112273 were comparable in UC and RMS patients.

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