Renal Impairment Study Research Articles

Simulating Healthy Participant Pharmacokinetics for Renal and Hepatic Impairment Studies: Retrospective Assessment of the Approach

The recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.Graphical

Re-discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions.

One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.

Pharmacokinetics of Edoxaban 15 mg in Very Elderly Patients with Nonvalvular Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Study.

We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk. This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies. The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 (n = 427) and 93.3 ± 57.8 ng/mL (n = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 (n = 79; 12.4 ± 12.1 and n = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group (n = 83; 25.1 ± 36.6 and n = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study (n = 39; 18.4 ± 11.2 and n = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not. PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight.

Can non-renal clearance and/or bioavailability of drugs be assessed reliably in renal impairment studies with oral drug administration?

The causes for the variable susceptibility of renal clearance (CLr) and bioavailability (F) of drugs in renal impairment are still unknown. We investigated whether the impact of chronic kidney disease (CKD) on non-renal clearance (CLnr) or F can be appraised when drug administration is by the oral route only in dedicated renal impairment studies (DRIS), as is routinely done when developing drugs intended for oral use. A literature search on DRIS administering drugs orally only or orally and intravenously was conducted. Seven drugs administered orally only with notable CLnr and 2 drugs administered by the oral and intravenous routes with negligible CLnr were identified. Regressions of oral clearance (CL/F), normalized by absolute bioavailability in healthy subjects (F1), on CLr were performed for the drugs with notable non-renal elimination to determine the impact of CKD on CLnr. Regressions of CL/F and CL on CLr were conducted for the drugs with negligible CLnr to determine F. Excessive variability in CL/F and CLr precluded evaluation of CLnr for 1 drug with notable CLnr and F1 < 0.01. A categorization based on the susceptibility of CLnr to CKD appeared possible for the 6 drugs with notable non-renal elimination if the parameters of the F1 normalized regressions of CL/F on CLr are taken at face value, i.e., if equality of F and F1 is assumed. However, the true relationship between F and F1 in subjects with varying renal function is unknowable for drugs with significant CLnr when administered orally only. F of drugs with significant CLnr may be altered by a reduced activity of uptake-transporters and/or enzymes so that in renal impaired subjects both absorption and first pass metabolism of intact drug may be reduced relative to healthy subjects, making it impossible to predict whether F in the former or latter population is greater. Bioavailability of drugs with negligible CLnr may depend primarily on the integrity of uptake-transporters so that F in healthy subjects is expected to be greater than in renal impaired subjects. Apparently accurate estimates of F for drugs with negligible CLnr may be obtained from DRIS with oral administration by using the reciprocal of the slope of the regressions. A reliable assessment of the impact of CKD on CLnr for drugs with significant non-renal elimination requires information after oral and intravenous administration in the same DRIS study. However, apparently accurate estimates of F for drugs with negligible non-renal elimination may be obtained in DRIS with oral drug administration only, but validation of the proposed method with other drugs exhibiting negligible non-renal elimination and variable F1 is required.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady‑state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady‑state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Population Pharmacokinetics in Hepatic and Renal Impairment and PBPK Drug-Drug Interaction Simulations of Asciminib, a Novel Tyrosine Kinase Inhibitor in Chronic Myeloid Leukemia in Chronic Phase

Introduction: Asciminib, a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP), has been recently approved by the FDA for adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs), as well as adult patients with Ph+ CML-CP with the T315I mutation. The recommended asciminib doses for patients with Ph+ CML-CP without the T315I mutation are 40 mg twice daily (BID), which is the dose tested in the pivotal phase III study (ASCEMBL), and a more patient-centric dose of 80 mg once daily (QD). For patients with the T315I mutation, the approved dose of asciminib is 200 mg BID. All asciminib drug-drug interaction (DDI) and hepatic and renal impairment studies were conducted at single or multiple doses of 40 mg. Here, we aim to assess the clinical impact of hepatic and renal impairment and of DDIs on the pharmacokinetics (PK) of asciminib and provide recommendations for eventual necessary dose adjustments. Methods: Organ impairment effect was quantified using population pharmacokinetics (PopPK), while DDIs were predicted using physiologically-based pharmacokinetics (PBPK). A 2-compartment PopPK model with a delayed first-order absorption and first-order elimination was developed for asciminib (Li et al. Clin Pharmacokinet, 2022). The original analysis included pooled PK data from patients receiving asciminib at 10−200 mg BID (in the phase I dose-finding study, NCT02081378) or 40 mg BID (in the phase III study ASCEMBL, NCT03106779), and identified baseline absolute glomerular filtration rate (aGFR), nominal total daily dose, body weight and formulation as significant covariates affecting asciminib PK. The model has been further extended to describe patients with renal (based on aGFR) or hepatic (based on Child-Pugh class) impairment, using data from two phase I PK studies in patients with renal (NCT03605277) or hepatic (NCT02857868) impairment. A PBPK model was developed and validated for asciminib using SimCYP v19.1. A stepwise "middle out” approach was used leveraging in vitro, in silico and in vivo data. The PBPK model was validated using single and multiple dose PK at 20‒400 mg daily dose as well as clinical DDI and PK data in patients with organ impairment. Comprehensive DDI scenarios and PK in patients with hepatic and renal impairment, which had not been clinically tested, were simulated at the different recommended doses of asciminib (40 mg BID, 80 mg QD, 200 mg BID). Results: There was no significant impact of hepatic function on asciminib exposure; a non-significant trend to lower clearance was observed in patients with severe hepatic impairment. The PopPK derived steady-state exposures (measured as area under the curve [AUC]0-24h) for patients with severe hepatic impairment were almost identical for both dosing regimens (40 mg BID: 13,018 ng*h/mL, 80 mg QD: 13,020 ng*h/mL), and only marginally higher than those of patients with normal hepatic function (12,638 ng*h/mL and 12,646 ng*h/mL, respectively), well within the therapeutic window of asciminib. Renal function assessment showed that clearance was slightly decreased in patients with renal impairment, although this was not clinically relevant. For both 80 mg QD and 40 mg BID, the median predicted AUC0-24h and maximum plasma concentration (Cmax) for severe renal impairment were 60% and 40% higher, respectively, than those of a typical individual with normal renal function. However, this difference is not considered to be clinically relevant given the relatively flat exposure-safety relationship over a 5-fold difference in exposure. The PBPK model predicted no drug interaction that would significantly impact the PK of asciminib (as a victim) or of other substrates (as a perpetrator). Overall, asciminib exposure was weakly affected by interactions with inducers and inhibitors as a victim (Figure 1B) and was predicted to be a weak inhibitor of CYP3A4 and P-gp at all tested doses and a weak to moderate inhibitor of CYP2C9 as a perpetrator (Figure 1A). Conclusions: Hepatic or renal impairment does not have a clinically significant impact on the PK of asciminib. Hence, dose adaptations for patients with hepatic or renal impairment are not warranted. Overall, asciminib has a manageable DDI risk at all recommended doses. Sponsor: Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non-orphan drugs approved by the FDA.

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food-drug interaction, drug-drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug-drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs.

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2'-MOE and Phosphorothioate Modified Antisense Oligonucleotides.

The pharmacokinetics (PK) of 2'-O-methoxyethyl and phosphorothioate antisense oligonucleotides (ASOs), with or without N-acetyl galactosamine conjugation, have been well characterized following subcutaneous or intravenous drug administration. However, the effect of organ impairment on ASO PK, primarily hepatic or renal impairment, has not yet been reported. ASOs distribute extensively to the liver and kidneys, where they are metabolized slowly by endo- and exonucleases, with minimal renal excretion as parent drug (<1%-3%). This short review evaluated the effect of organ impairment on ASO PK using 3 case studies: (1) a phase 1 renal impairment study evaluating a N-acetyl galactosamine-conjugated ASO in healthy study participants and study participants with moderate renal impairment, (2) a phase 2 study evaluating an unconjugated ASO in patients with end-stage renal disease; and (3) a phase 3 study evaluating an unconjugated ASO, which included patients with mild hepatic or renal impairment. Results showed that patients with end-stage renal disease had a mild increase (≈34%) in total plasma exposure, whereas mild or moderate renal impairment showed no effect on plasma PK. The effect of hepatic impairment on ASO PK could not be fully evaluated due to lack of data in moderate and severe hepatic impairment study participants. Nonetheless, available data suggest that mild hepatic impairment had no effect on ASO exposure.

Concordance of Exposure Changes Because of Renal Impairment Between Results of Dedicated Renal Impairment Studies and Population Pharmacokinetic Predictions.

This analysis compared the results from noncompartmental analysis and population pharmacokinetic (PopPK) predictions of exposure changes in patients with renal impairment (RI) for 27 new molecular entities (NMEs) approved between 2000 and 2015. Renal function was identified as a covariate in the final PopPK model for 17 NMEs. The final PopPK model was used to simulate (n = 1000 replicates/individual) the results of a dedicated PK study in subjects with renal impairment. For the majority of NMEs, concordance between observed, and predicted area under the curve (AUC) geometric mean ratio (GMR) was observed (ie, in 17, 11, and 11 NMEs for mild, moderate, and severe renal impairment groups, respectively, the observed and predicted AUC GMR were within the same fold of change). Inclusion of colinear covariates in the PopPK model appeared to be the major driver for the NMEs for which there was discordance. PopPK, when done properly, is a valuable tool for supporting labeling recommendations for subjects with renal impairment.

Abstract 1365: Virtual healthy control matching for renal impairment studies: A case study with glasdegib

Abstract Background: Clinical development of drugs often requires many pharmacokinetic (PK) studies in healthy volunteers that are conducted prior to renal or hepatic impairment studies. The present analysis evaluated the feasibility of using PK data from healthy participants in other clinical studies as ‘virtual' matched healthy controls for a study of glasdegib PK in participants with moderate to severe renal impairment. Methods: Data from 83 subjects treated with a single oral dose of 100 mg glasdegib in four healthy volunteer studies was used. Virtual healthy controls were selected by renal function (estimated glomerular filtration rate (eGFR) &amp;gt;90mL/min) and matched by age (± 20 yr) and body weight (± 15 kg) to the renal impairment participants from the glasdegib renal impairment study. One-way analysis of variance was used to compare log transformed PK parameters for each renal impairment group to the normal or virtual-normal renal function groups. Post-hoc pairwise comparisons between groups were performed using Tukey's method. Results: A total of 9 healthy matched control subjects were included in the ‘virtual' normal renal function group. Adjusted geometric mean ratios and 90% CI for comparisons between renal impairment groups and normal or ‘virtual' normal renal function groups produced similar results (Table 1). Conclusions: Using data from healthy volunteers in earlier clinical studies to create a ‘virtual' matched normal renal function group for a renal impairment study in glasdegib produced similar results to the prospectively enrolled normal renal function group. Use of virtually matched healthy controls may be a viable option to leverage already available data efficiently and minimize exposure of healthy participants to oncology drugs. Statistical summary of renal function group comparisons, with normal or virtual normal as referenceParameters and Comparisons (Test vs. Reference)Adjusted Geometric mean (Test)Adjusted Geometric Mean (Reference)Adjusted Geometric Mean Ratio (%) (Test/Reference)Adjusted Geometric Mean Ratio (%) 90% CIAUCinf (ng*hr/mL)Moderate Impairment vs Normal Renal Function19641.19601.9204.56(135.85, 308.00)Moderate Impairment vs Virtual Normal Renal Function19641.19410.6208.71(149.42, 291.54)Severe Impairment vs Normal Renal Function19427.09601.9202.33(131.72, 310.79)Severe impairment vs Virtual Normal Renal Function19427.09410.6206.44(144.94, 294.04)AUClast (ng*hr/mL)Moderate Impairment vs Normal Renal Function19181.59474.6202.45(129.03, 317.65)Moderate Impairment vs Virtual Normal Renal Function19181.59286.5206.55(142.82, 298.73)Severe Impairment vs Normal Renal Function16630.89474.6175.53(111.87, 275.41)Severe impairment vs Virtual Normal Renal Function16630.89286.5179.09(123.83, 259.01)Cmax (ng/mL)Moderate Impairment vs Normal Renal Function1082.0791.2136.76(84.00, 222.65)Moderate Impairment vs Virtual Normal Renal Function1082.0789.4137.07(91.39, 205.59)Severe Impairment vs Normal Renal Function950.1791.2120.09(73.76, 195.51)Severe impairment vs Virtual Normal Renal Function950.1789.4120.36(80.25, 180.53)1The Adjusted geometric mean ratios (and 90% CIs) are expressed as percentages.2CI=confidence interval. Citation Format: Brian Reilly, Naveed Shaik, Swan Lin. Virtual healthy control matching for renal impairment studies: A case study with glasdegib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1365.

Risk of nephrogenic systemic fibrosis in patients with impaired renal function undergoing fixed-dose gadoxetic acid-enhanced magnetic resonance imaging.

To assess the risk of nephrogenic systemic fibrosis (NSF) in patients with renal impairment undergoing gadoxetic acid-enhanced magnetic resonance imaging. This retrospective study included patients who had an estimated glomerular filtration rate (eGFR) below 60mL/min per 1.73m2 or had undergone dialysis around the time of gadoxetic acid exposure from January 2010 to November 2019. All patients received at least one intravenous injection of gadoxetic acid at a fixed dose of 2.5mmol. The primary endpoint was the development of NSF after exposure to gadoxetic acid based on Girardi's clinicopathological scoring system. A total of 204 patients with renal impairment received 424 injections of gadoxetic acid, of which 131 and 54 had an eGFR of 30-59 and < 30mL/min per 1.73m2, respectively, and 19 had undergone hemodialysis. Eighty-two patients received multiple injections, with 23 receiving five or more injections. The dose of each exposure ranged from 0.02 to 0.07mmol/kg and the cumulative doses ranged from 0.02 to 0.45mmol/kg. Thirty-three patients had concomitant Child-Pugh class B or C cirrhosis. No NSF was detected during follow-up (median 20months; range 6days to 111months). The upper bound of the 95% confidence interval for NSF risk was 2.2% and 1.1% per patient and examination, respectively. No NSF was detected in this study. However, it is premature to ascertain the risk of NSF using gadoxetic acid in patients with renal impairment and further studies are warranted.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Temsavir, the Active Moiety of Fostemsavir.

The oral prodrug fostemsavir (GSK3684394, formerly BMS-663068) is an antiretroviral treatment for HIV-1. Fostemsavir is metabolized to its active moiety, temsavir, a first-in-class HIV-1 attachment inhibitor that binds to the viral envelope glycoprotein 120. Long-term antiretroviral therapy, the resulting longer life expectancy, and/or certain coinfections can increase the risk of chronic liver and kidney disease in HIV-1-infected individuals. Two studies were conducted to collectively evaluate the impact of renal and hepatic impairment on temsavir pharmacokinetics (PK) and safety following a single dose of a 600-mg extended-release fostemsavir tablet. There was no clinically meaningful effect of renal or hepatic impairment on temsavir PK, although renal clearance decreased with increasing renal impairment from moderate to severe, and exposure (maximum concentration and area under the plasma concentration-time curve from time 0 to infinity) tended to increase with increasing severity of hepatic impairment. No clinically meaningful effect of hemodialysis on temsavir PK parameters was observed. Fostemsavir was generally safe and well tolerated by treated subjects. Most adverse events (AEs) were mild, with the exception of 1 patient in the renal impairment study who discontinued due to 2 serious AEs unrelated to the study drug. No other treatment-emergent serious AEs occurred, and no other AEs leading to discontinuation were reported. Overall, these results suggest that fostemsavir can be used without dose modification in subjects with mild to severe renal impairment, including those with end-stage renal disease on hemodialysis, and in subjects with mild to severe hepatic impairment.

Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function.

PurposeRevefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592).Subjects and methodsThe renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events.ResultsIn the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration–time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively.ConclusionSystemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Effect of Hepatic Organic Anion-Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver-Targeted Glucokinase Activator: A Model-Based Evaluation.

PF-04991532 ((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato-selectivity via organic anion-transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF-04991532 oral pharmacokinetics. Cyclosporine (600mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF-04991532 AUC values were ~2.3-fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically-based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter-mediated disposition based on in vitro inputs, and verified using first-in-human data, indicated the key role of OATP-mediated hepatic uptake in the systematic and target-tissue exposure of PF-04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~35%) and renal organic anion transporter (OAT)3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter-mediated disposition.

Child-Pugh versus NCI-ODWG categorization for hepatic impairment studies - observations from a renal and hepatic impairment study with darolutamide, a novel investigational androgen receptor antagonist

Child-Pugh versus NCI-ODWG categorization for hepatic impairment studies - observations from a renal and hepatic impairment study with darolutamide, a novel investigational androgen receptor antagonist

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies

IntroductionAmenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.MethodsThese studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.ResultsIn the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.ConclusionThe findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearanceFundingAstellas Pharma.

O56-2 - Efficacy of Add-on low Dose Versus High Dose of Tolvaptan to Furosemide on Congestive Heart Failure with Advanced Kidney Dysfunction

Aims: This study compared the efficacy of add-on low dose of tolvaptan (TLV) tofurosemide (FUR) with that of add-on high dose of TLV to FUR on heart failure (HF)patients with advanced kidney dysfunction (estimated glomerular filtration rate, eGFR; <45 mL/min/1.73 m2). Methods and Results: This study analyzed two clinical trial data from the Kanagawa Aquaresis Investigators Trial of TLV on HF patients with Renal Impairment (K-STAR) study and the pharmacokinetic/pharmacodynamic (PK/PD) study of TLV in HF patients with advanced kidney dysfunction. The K-STAR study was a multicenter, open-labeled, randomized and controlled prospective clinical study; the PK/PD study was a single center, open-label, single-dose study. The present study patients were divided into the TLV 7.5 mg (n = 32) or TLV 15 mg (n = 25) group. The urine volume significantly increased in the CKD stage 3 group (TLV 15 mg, 4572 mL; TLV 7.5 mg, 4114 ml) rather than the CKD stage 4,5 group(TLV 15 mg, 3557 mL; TLV 7.5 mg, 3030 ml; P = .01) . No significant differences in serum creatinine level or worsening renal function were observed at baseline and 48 hours after treatment. Conclusion: Add-on TLV 15 mg to FUR was effective to increase urine volume in congestive HF patients with CKD stage 4,5 group within 48 hours after administration. We recommend that TLV should be initiated at the lower doses (7.5 mg) in CKD stage 3 group.

Anti-PD-1 therapy in patients with end-stage renal disease on dialysis: A single-center case series.

e14553 Background: Anti-PD-1 monoclonal antibodies (PD1) have clinical activity in several solid tumors. However, experience treating dialysis pts with PD1 is limited. Dosage adjustments are not recommended for renal impairment but PK studies did not include pts with ESRD on dialysis. Two case reports have described objective responses and a tolerable AE profile. We sought to explore the safety and efficacy of PD1 in such pts. Methods: In this single-center case series, we identified 4 pts with ESRD on dialysis who were treated with PD1 between 10/2014 to 11/2016. Data regarding clinical history, PD1 dosing, dialysis regimen, treatment (tx) response, and toxicity were collected. Results: Four pts were evaluable for data collection. Two pts had metastatic renal cell carcinoma (mRCC) and 2 others had unresectable cutaneous squamous cell carcinoma (cuSCC). Age at tx ranged from 66 to 71; all 4 pts were male. Number of doses ranged from 4 to 8. Two pts with mRCC received nivo 3 mg/kg q2wk after dialysis. Two pts with cuSCC received pembro 2 mg/kg q3wk after dialysis; dosing was extended to q4wk for 1 pt due to persistent grade (G) 2 fatigue. Three pts were on hemodialysis 3 times a wk and 1 pt was on peritoneal dialysis. Time to progression was 3 months for 1 mRCC pt and could not be determined for the other mRCC pt who had a PR but died from possible tx-related causes. Two cuSCC pts are still receiving pembro with PR at time of analysis. Immune-related AEs were seen in all 4 pts, including 2 incidences of G2 fatigue and 1 incidence each of G2 rash and G3 pneumonitis.One pt developed acute encephalitis after 4 doses of nivo that improved with steroids but was ultimately fatal. Conclusions: This single-center case series highlights the efficacy and AE profile of PD1 for pts with ESRD on dialysis. While this is a small series, there was significant anti-tumor activity in this group of pts. Despite the reported favorable AE profile of PD1, one pt had a serious and mortal AE that may have been related to tx. This should be considered in future studies. High molecular weight of PD1 suggests these agents are not removed by dialysis but we were limited by lack of PK data. Our experience adds to the 2 cases in the literature. Further studies are warranted in larger cohorts.

Effect of the SGLT2 Inhibitor Dapagliflozin on Potassium Levels in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

IntroductionHyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM).MethodsFourteen randomized, placebo-controlled, double-blind T2DM studies were analyzed: pooled data from 13 studies of ≤24 weeks’ duration (dapagliflozin 10 mg, N = 2360; placebo, N = 2295); and one 52-week moderate renal impairment study in patients with baseline eGFR ≥30 to <60 mL/min/1.73 m2 (dapagliflozin 10 mg, N = 85; placebo, N = 84). Central laboratory serum potassium levels were determined at each study visit.ResultsNo clinically relevant mean changes from baseline in serum potassium ≤24 weeks were reported for dapagliflozin 10 mg [−0.05 mmol/L; 95% confidence interval (CI) −0.07, −0.03] versus placebo (−0.02 mmol/L; 95% CI −0.04, 0.00) in the pooled population or in the renal impairment study (−0.03 mmol/L; 95% CI −0.14, 0.08 vs. −0.02 mmol/L; 95% CI −0.13, 0.09, respectively). The incidence rate ratio for serum potassium ≥5.5 mmol/L over 24 weeks for dapagliflozin 10 mg versus placebo was 0.90 (95% CI 0.74, 1.10) in the pooled population; with no increased risk in patients receiving ARBs/ACE inhibitors, or potassium-sparing diuretics, or in those with moderate renal impairment. Slightly more patients receiving dapagliflozin 10 mg had serum potassium ≤3.5 mmol/L versus placebo (5.2% vs. 3.6%); however, no instances of serum potassium ≤2.5 mmol/L were reported.ConclusionDapagliflozin is not associated with an increased risk of hyperkalemia or severe hypokalemia in patients with T2DM.FundingBristol-Myers Squibb and AstraZeneca.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0150-y) contains supplementary material, which is available to authorized users.

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?

Are We Getting the Best Return on Investment From Clinical Drug-Drug Interaction Studies?