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Novel drugs such as immunomodulators and proteasome inhibitors have improved the survival of patients with multiple myeloma. Like all therapeutic agents, appropriate dosing based on metabolism and clearance is important to maintain efficacy while avoiding toxicity. Hepatic impairment (HI) in multiple myeloma patients is rare but well described either due to disease or therapy-related factors. However, limited data are available on the appropriate use and dosing of the novel agent therapeutics in myeloma patients with HI. Furthermore, data on HI secondary to the novel agent toxicity are also sparse. This systematic review highlights the evidence on the use of novel agents like thalidomide, lenalidomide, pomalidomide, bortezomib and carfilzomib in patients with HI as well as their associated hepatic toxicities.

Purpose To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. Methods Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. Results A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC 0-24 ) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC 0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC 0-24 , and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. Conclusion In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC 0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

The evaluation of transporter-mediated drug–drug interactions (DDIs) during drug development and post-approval contributes to benefit–risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [C ], area under the curve [AUC] and AUC ) and secondary PK parameters (AUC , apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [T ], and half-life [T ]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis. C of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). C in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUC for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUC was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.

Background Apixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments. Methods This study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model’s fit performance. Results Doses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure. Conclusion The findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations.

To evaluate the effects of mild and moderate hepatic impairment on the pharmacokinetics and safety of SHR0302. This open-label, parallel-group study enrolled 24 Chinese subjects, including subjects with normal hepatic function and those with mild or moderate hepatic impairment (8 per group). All subjects received a single oral dose of SHR0302 (8 mg). Plasma PK parameters of SHR0302 and its metabolite, SHR161279, were assessed and compared across groups. Safety was evaluated throughout the study. Mild hepatic impairment had minimal effect on the exposure of SHR0302. In subjects with moderate hepatic impairment, the C of SHR0302 was approximately 17% lower than that in subjects with normal hepatic function, whereas AUC and remained generally unchanged. Meanwhile, exposure to SHR161279 decreased in both hepatic impairment groups, with reductions of approximately 21%-38%. SHR0302 was generally safe after single-dose administration. Eight subjects (8/24, 33.3%) experienced treatment-emergent adverse events (TEAEs). No serious adverse events were reported. Mild and moderate hepatic impairment had minimal effect on SHR0302 exposure. Based on the single-dose pharmacokinetic and safety data, dose adjustment of SHR0302 may not be necessary in patients with mild or moderate hepatic impairment. https://clinicaltrials.gov/, identifier NCT04293029.

YZJ-1139 (Fazamorexant) is a dual orexin receptor antagonist in development for adult insomnia. This study assessed the impact of hepatic impairment on Fazamorexant's pharmacokinetic safety, and tolerability to guide clinical dosing. This study used a non-randomized, open-label, single-dose design. Patients with mild or moderate hepatic impairment (Child-Pugh class A or B) and healthy subjects (n = 8 per group) received a single oral 20 mg dose of Fazamorexant. In total, 24 participants were enrolled and completed the study. In subjects with mild hepatic impairment, the geometric mean ratios (90% CI) of Fazamorexant plasma C , AUC , and relative to those with normal hepatic function were 97.82% (77.41%-123.60%), 145.22% (96.83%-217.79%), and 145.43% (97.70%-216.47%), respectively. In moderate impairment, the corresponding values for C , AUC , and were 104.68% (82.85%-132.28%), 153.41% (102.29%-230.07%), and 154.50% (103.79%-229.97%). Hepatic impairment did not significantly alter the peak time. Fazamorexant was generally well tolerated. Fazamorexant showed good safety and minimal impact of hepatic impairment on C , but AUC increased by approximately 50% in patients with mild or moderate hepatic impairment.

A common challenge in conducting phase 1 studies that assess the impact of organ impairment on the pharmacokinetics of a drug is the recruitment of a demographically matched control group. The work presented here evaluated alternative approaches for generating control groups in these studies. Available phase 1 data from the upadacitinib and elagolix clinical programs were leveraged as case studies. A statistical matching approach and a population pharmacokinetic model‐based approach were evaluated retrospectively for these programs' hepatic and renal impairment clinical studies. Geometric mean ratios of logarithmically transformed Cmax and AUCinf were used to compare exposure in organ impairment groups to respective matched or virtual control groups. In the statistical matching approach, the genetic matching algorithm using Mahalanobis distance showed that external control groups were adequately demographically balanced across all impairment groups of the study except for age. A 3:1 k‐match approach minimized the prediction error between matched and reference in‐study results for both case studies, resulting in differences in geometric mean ratios ranging from −19% to 3% and −27% to 40% for upadacitinib and elagolix, respectively, compared to in‐study controls. Similarly, the population pharmacokinetic approach used models developed from phase 1 data in healthy participants and found that the results were generally comparable to the in‐study results, with differences in geometric mean ratios ranging from −30% to 17% and −24% to 41% for upadacitinib and elagolix, respectively. These analyses demonstrate that both approaches may be viable alternatives to assess the impact of organ impairment on pharmacokinetics.

Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment. This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data. Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults. The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.

Purpose5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment.MethodsModels including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment.ResultsThe PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes′ activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics.ConclusionsPBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios.