We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anti-cytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AA) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AA have primarily evaluated the CYP3A5*3 variant; however, there are common nonfunctional variants in AA (CYP3A5*6 and CYP3A5*7) which do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AA are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AA using a development and validation cohort. Time posttransplant, steroid and antiviral use, age, CYP3A5*1, *3, *6 and *7 alleles were significant towards clearance. This study is the first to develop an AA specific genotype-guided tacrolimus dosing model to personalize therapy.

Background: CD73 is an ectonucleotidase that converts adenosine monophosphate to adenosine, a potent immunosuppressive soluble mediator that inhibits the cytotoxic function of CD8+ T cells and natural killer cells while promoting proliferation of immunosuppressive cells. BMS-986179 is a high-affinity antibody that inhibits CD73 enzymatic activity and downregulates its expression on tumor cells. Blockade of CD73 enhanced the antitumor activity of anti-PD-1 in preclinical models (Barnhart BC, et al. Cancer Res. 2016;76(14 suppl) [abstract 1476]). Here we describe preliminary results of the first-in-human phase 1/2a study of BMS-986179 + nivolumab (NIVO) in patients (pts) with advanced solid tumors (NCT02754141). Methods: Pts with ≥ 1 prior therapy were treated in this open-label, dose-escalation and -expansion study. Escalation began with a 2-week monotherapy lead-in, in which pts received BMS-986179 150-1600 mg IV QW followed by BMS-986179 (same dose) IV QW + NIVO 240 mg IV Q2W. Pharmacokinetics (PK), pharmacodynamics (PD), safety, and preliminary antitumor activity were evaluated. PD analyses included immunohistochemistry, enzyme activity assays in tumor biopsies, and evaluation of receptor occupancy and soluble CD73 in peripheral blood. Results: As of the Dec 19, 2017, data cutoff, 59 pts were treated with BMS-986179 ± NIVO during dose escalation. PK of BMS-986179 was nonlinear at lower doses due to target-mediated drug disposition, and exposure increased proportionally from 1200 to 1600 mg. BMS-986179 demonstrated complete and persistent CD73 target engagement in the tumor and periphery at all doses. Treatment-related AEs (TRAEs) were observed in 30 of 52 pts (58%) who received the combination, with no clear dose relationship. Only 8 pts (15%) experienced grade 3 TRAEs, and 1 discontinued treatment due to a TRAE (grade 3 increased ALT). Both the monotherapy lead-in and the combination were well tolerated, with no grade 4 TRAEs and no treatment-related deaths. BMS-986179 efficiently inhibited CD73 enzyme activity in the tumor vasculature and tumor cells at all doses, without dose dependency. Overall, 7 pts with head and neck, pancreatic, prostate, anal, and renal cancer achieved confirmed partial responses and 10 pts had stable disease. Conclusions: BMS-986179 + NIVO was well tolerated, with CD73 target engagement in the tumor and periphery and a safety profile similar to that of NIVO monotherapy. The combination demonstrated preliminary antitumor activity. These data support the ongoing evaluation of this combination in pts with advanced solid tumors. Citation Format: Lillian L. Siu, Howard Burris, Dung T. Le, Antoine Hollebecque, Neeltje Steeghs, Jean-Pierre Delord, John Hilton, Bryan Barnhart, Emanuela Sega, Kinjal Sanghavi, Anke Klippel, Cyrus Hedvat, Ed Hilt, Mark Donovan, Adrianna Gipson, Paul Basciano, Jennifer Postelnek, Yue Zhao, Raymond P. Perez, Richard D. Carvajal. Preliminary phase 1 profile of BMS-986179, an anti-CD73 antibody, in combination with nivolumab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT180.

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and for the treatment of melanoma, renal cell carcinoma, and colorectal cancer in combination with nivolumab. Ipilimumab time-varying clearance (CL) was assessed by a population pharmacokinetics (PPK) model developed using statistically significant covariates identified in a previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.3-10 mg/kg alone or in combination with nivolumab in 16 clinical trials were analyzed. Ipilimumab CL decreased over time; the change in CL was greater in patients treated with nivolumab combination than ipilimumab alone and in responders vs. nonresponders. Time-varying covariates including body weight, lactate dehydrogenase, albumin, and performance status were evaluated on change in ipilimumab CL. In addition, ipilimumab CL was similar across different tumor types, nivolumab dosing regimens, and lines of therapy. These data suggest an association of ipilimumab CL with disease severity.