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Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6–9 weeks followed by a less frequent dosing regimen, once every 2–4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure–efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure–response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma ( p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.

Extracellular vesicles (EVs) are under evaluation as therapeutics or as vehicles for drug delivery. Preclinical studies of EVs often use mice or other animal models to assess efficacy and disposition. However, as most EVs under evaluation are derived from human cells, they may elicit immune responses which may contribute to toxicities or enhanced EV clearance. Furthermore, EVs from different cell sources or EVs comprising various cargo may differ with respect to immunogenicity or toxicity. To assess EV-induced immune response and toxicity, we dosed C57BL/6 mice with EVs intravenously and intraperitoneally for 3 weeks. EVs were harvested from wild type or engineered HEK293T cells which were modified to produce EVs loaded with miR-199a-3p and chimeric proteins. Blood was collected to assess hematology, blood chemistry, and immune markers. Spleen cells were immunophenotyped, and tissues were harvested for gross necropsy and histopathological examination. No signs of toxicity were observed, and minimal evidence of changes in immune markers were noted in mice dosed with engineered, but not with wild type EVs. This study provides a framework for assessment of immunogenicity and toxicity that will be required as EVs from varying cell sources are tested within numerous animal models and eventually in humans.

Concentrative nucleoside transporters (CNTs) are active nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here we identify a role of CNT1 in the renal reabsorption of nucleosides. Deletion of CNT1 in mice increases the urinary excretion of endogenous pyrimidine nucleosides with compensatory alterations in purine nucleoside metabolism. In addition, CNT1 KO mice exhibits high urinary excretion of the nucleoside analog gemcitabine (dFdC), which results in poor tumor growth control in CNT1 KO mice harboring syngeneic pancreatic tumors. Interestingly, increasing the dFdC dose to attain an area under the concentration-time curve level equivalent to that achieved by wild-type (WT) mice rescues antitumor efficacy. The findings provide new insights into how CNT1 regulates reabsorption of endogenous and synthetic nucleosides in murine kidneys and suggest that the functional status of CNTs may account for the optimal action of pyrimidine nucleoside analog therapeutics in humans. Concentrative nucleoside transporters (CNTs) are cellular nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here the authors show a role of CNT1 in the renal reabsorption of endogenous and synthetic nucleosides.

Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4 , CYP3A5 , and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care ( p < 0.001) and throughout the entirety of the study period ( p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient ( p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.

Aspirin is one of the most commonly used medications in pregnancy, particularly for the prevention of hypertensive disorders. Despite aspirin's widespread use in pregnancy for preeclampsia prevention, its pharmacokinetics (PK) across all trimesters remain poorly characterized, complicating optimal dosing recommendations. To develop a pregnancy‐specific physiologically based pharmacokinetic (PBPK) model for aspirin that could be individualized to patient‐specific parameters, illustrating differences in aspirin PK across the different trimesters of pregnancy. A PBPK model was developed using GastroPlus (a mechanistically driven simulation software) for nonpregnant and pregnant people at each trimester of pregnancy. The nonpregnant PBPK model was first established and validated against existing data from healthy adult volunteers. Once validated, the model was adapted for pregnant people and verified using observed pharmacokinetic profiles. The simulated PK parameters of aspirin in pregnant and nonpregnant women closely matched the clinical observations reported in the literature, with fold errors ≤ 1.04 (less than 1.5 is considered an acceptable simulation model). The predicted systemic exposure (AUC0‐24h) of salicylic acid (SA), the active metabolite of aspirin decreased throughout gestation, showing a reduction of approximately 20% at 10 weeks and 30% at 40 weeks. An increase in clearance was observed as gestation progressed. The model predicted a modest decrease of 10% in systemic exposure in pregnant women and a 20% increase in fetal exposure to SA as pregnancy progresses. A PBPK model using GastroPlus was developed to describe the PK and pharmacodynamics of aspirin in both pregnant and nonpregnant healthy adults.

Patients with cancer-cachexia display a general resistance to Immune Checkpoint Inhibitor (ICI) therapy, as well as an elevated baseline catabolic clearance (CL) of ICIs, which serves as a prognostic indicator of overall survival independent of dose and drug exposure. Increased rate of ICI CL is present in the Lewis Lung Carcinoma (LLC) murine model of cachexia, but absent in the non-cachectic MC38 model. Fc-Gamma Receptors (FcγRs) bind the Fc portion of antibodies and can impact ICI anti-tumor efficacy. A pharmacokinetic study of human IgG1 (hIgG1) and hIgG1 with D265A (D265A) mutation, to abrogate all FcγR binding, was performed in mice that were either LLC tumor bearing (TB) or tumor free (TF). Immunofluorescence studies using fluorescence conjugated anti-human IgG were conducted to detect and localize infused hIgG1 in the mouse liver. To further investigate, FcγRIIb knockout mice were utilized in pharmacokinetic studies with hIgG. CL of both IgG1 and D265A significantly increased in LLC TB mice compared to TF controls, however the CL of D265A was significantly lower compared to hIgG1 in LLC TB mice. Immunofluorescence image of mouse livers portrays colocalization of the administered hIgG1 and FcγRIIb in liver sinusoidal endothelial cells (LSEC), as well as upregulated hepatic expression of FcγRIIb in LLC TB. However, hIgG1 CL was unaffected by whole body knockout of FcγRIIb. Reduced CL of D265A versus IgG1 in LLC TB mice, but not TF mice, suggests FcγRs are involved in catabolic CL of IgG antibodies in the presence of LLC tumors and cancer cachexia. This suggest that in the presence of LLC tumors, changes in FcγR expression and/or function lead to significantly altered antibody CL mediated by FcγR. This apparent role of FcγRs in antibody catabolism cannot be solely explained by FcγRIIb, but instead suggests the significance of other FcγRs in cachexia-associated increases in antibody CL.

As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Phelps et al., 2016) that described how we intended to replicate selected experiments from the paper ‘Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs’ (Tay et al., 2011). Here, we report the results. We found depletion of putative PTEN competing endogenous mRNAs (ceRNAs) in DU145 cells did not impact PTEN 3’UTR regulation using a reporter, while the original study reported decreased activity when SERINC1 , VAPA , and CNOT6L were depleted (Figure 3C; Tay et al., 2011). Using the same reporter, we found decreased activity when ceRNA 3’UTRs were overexpressed, while the original study reported increased activity (Figure 3D; Tay et al., 2011). In HCT116 cells, ceRNA depletion resulted in decreased PTEN protein levels, a result similar to the findings reported in the original study (Figure 3G,H; Tay et al., 2011); however, while the original study reported an attenuated ceRNA effect in microRNA deficient (Dicer Ex5 ) HCT116 cells, we observed increased PTEN protein levels. Further, we found depletion of the ceRNAs VAPA or CNOT6L did not statistically impact DU145, wild-type HCT116, or Dicer Ex5 HCT116 cell proliferation. The original study reported increased DU145 and wild-type HCT116 cell proliferation when these ceRNAs were depleted, which was attenuated in the Dicer Ex5 HCT116 cells (Figure 5B; Tay et al., 2011). Differences between the original study and this replication attempt, such as variance between biological repeats, are factors that might have influenced the results. Finally, we report meta-analyses for each result.

Patients with cancer cachexia display a general resistance to immune checkpoint inhibitor (ICI) therapy, and baseline ICI catabolic clearance is a predictive indicator for overall survival, independent of dose and drug exposure. Fc-gamma (FcγRs) and neonatal Fc receptors (FcRn) play key roles in ICI clearance and efficacy, and we aimed to determine the impact of cachexia, independent of tumor, on immune cell populations and their Fc receptor (FcR) expression in patients and in murine models of cancer, cachexia, and cancer cachexia. Immune cell populations and their FcR expression were measured in tumor-bearing and tumor-free mice, with/without cachexia, and from patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma. These measures, upon splenocytes and peripheral blood mononuclear cells (PBMCs) in mice and humans respectively, were compared with baseline ICI drug clearance and cachexia phenotype. Leukocyte populations and FcγR in mouse splenocytes displayed distinct expressional patterns when comparing across tumor and cachexia status. Univariate analyses revealed several correlations between FcγR expression on patient PBMCs and both ICI clearance and cachexia phenotype. Notably, FcRn expression was unchanged or slightly elevated in tumor-bearing mice and did not correlate with ICI clearance in murine splenocytes or patient leukocytes. Furthermore, immune cell populations and FcR expression were different among tumor types but did not differ in splenocytes of tumor-free mice with Activin A/IL-6 induced cachexia when compared with vector controls. These findings provide the first evidence that FcRs, critical for the efficacy and pharmacokinetics of many ICI and other IgG mAbs, are altered in a tumor-dependent manner. Furthermore, in the absence of a tumor, cachexia phenotype may not coincide with inflammation in the form of altered immune cell populations and elevated catabolic clearance of IgG mAbs, suggesting these features arise from properties intrinsic to the tumor.