Pharmacokinetics, Safety, and Efficacy of Letermovir for Cytomegalovirus Prophylaxis in Adolescent Hematopoietic Cell Transplantation Recipients.

INTRODUCTION: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients (R+). We report pharmacokinetics (PK), safety, and efficacy of letermovir in adolescent (12-18 years) allogeneic HCT recipients from an ongoing clinical study. METHODS: In this phase 2b, multicenter, open-label study (NCT03940586), 28 adolescents received 480 mg letermovir [240 mg with cyclosporin A (CsA)] once daily orally or intravenously. Blood was collected for intensive (n = 14) plasma concentrations of letermovir. Intensive PK data were used for dose confirmation. Target exposure range 34,400-100,000 h × ng/mL for pediatric median exposures was based on model-predicted phase 3 population PK simulations in adult HCT recipients. RESULTS: All participants were CMV-seropositive (body weight 28.7-95.0 kg). Of 12 PK-evaluable participants, 8 receiving 480 mg letermovir without CsA and 4 receiving 240 mg letermovir with CsA achieved exposures comparable to the adult exposure range. Exposure above the target but below the adult clinical program maximum was observed in 1 patient. Safety was consistent with previously described safety in adults. The proportion of participants with clinically significant CMV infection through week 24 post-HCT was comparable (24%) to that in the pivotal phase 3 study in adults (37.5%). CONCLUSIONS: Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults. Results support a letermovir dose of 480 mg (240 mg with CsA) in adolescent allo-HCT recipients.

Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease.

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.

Dose Optimization for Anticancer Drug Combinations: Maximizing Therapeutic Index via Clinical Exposure-Toxicity/Preclinical Exposure-Efficacy Modeling.

PURPOSE: Recommended phase II dose (RP2D) determination for combination therapy regimens is a constrained optimization problem of maximizing antitumor activity within the constraint of clinical tolerability to provide a wide therapeutic index. A methodology for addressing this problem was developed and tested using clinical and preclinical data from combinations of the investigational drugs TAK-117, a PI3Kα inhibitor, and TAK-228, a TORC1/2 dual inhibitor. EXPERIMENTAL DESIGN: Utilizing free fraction-corrected average concentrations, [Formula: see text] and [Formula: see text], which are the primary pharmacokinetic predictors of single-agent preclinical antitumor activity, a preclinical exposure-efficacy surface was characterized, allowing for nonlinear interactions between growth rate inhibition of the agents on a MDA-MB-361 cell line xenograft model. Logistic regression was used to generate an exposure-effect surface for [Formula: see text] and [Formula: see text] versus clinical toxicity outcomes [experiencing a dose-limiting toxicity (DLT)] in single-agent and combination dose-escalation studies. A maximum tolerated exposure curve was defined at which DLT probability was 25%; predicted antitumor activity along this curve was used to determine optimal RP2D. RESULTS: The toxicity constraint curve determined from early clinical data predicted that any clinically tolerable combination was unlikely to result in greater antitumor activity than either single-agent TAK-117 or TAK-228 administered at their respective MTDs. Similar results were obtained with 10 other cell lines, with one agent or the other predicted to outperform the combination. CONCLUSIONS: This methodology represents a general, principled way of evaluating and selecting optimal RP2D combinations in oncology. The methodology will be retested upon availability of clinical data from TAK-117/TAK-228 combination phase II studies.See related commentary by Mayawala et al., p. 6564.

Dose schedule optimization and the pharmacokinetic driver of neutropenia.

Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.

Preclinical pharmacokinetic/pharmacodynamic/efficacy relationships for alisertib, an investigational small-molecule inhibitor of Aurora A kinase.

PURPOSE: Alisertib (MLN8237) is an investigational inhibitor of Aurora A kinase (AAK). Aurora A plays an essential role in the regulation of spindle assembly and chromosome alignment during mitosis. Inhibition of Aurora A by alisertib in tissue culture has previously been demonstrated to lead to improper chromosomal alignment and disruption of spindle organization, resulting in a transient mitotic delay. The spindle organization defects induced by alisertib have been used to develop a pharmacodynamic (PD) assay for Aurora A inhibition based on the percentage of mitotic cells with proper chromosomal alignment at the metaphase plate (% aligned spindles, abbreviated as AS). The transient mitotic delay that occurs with AAK inhibition permits the use of the mitotic index (the fraction of cells in the population currently undergoing mitosis, abbreviated as MI) as an additional PD assay. When the two PD assays were used in Phase I clinical trials, the reduction in AS was strongly correlated with dose levels and exposures in patients from single time point PD measurements; however, MI failed to show any correlation. To further understand this clinical finding, we constructed PK/PD/efficacy models for AS and MI that can precisely capture the temporal dynamics of the PD markers from in vivo xenograft studies. METHODS: A PK/PD study was conducted using a single oral dose of alisertib at 3, 10, and 20 mg/kg in HCT-116 xenografts implanted subcutaneously in mice. An extravascular, two-compartmental pharmacokinetic (PK) model was used to describe the drug kinetics. Consistent with the mechanistic hypothesis for AAK inhibition, the PD biomarkers such as AS and MI were fitted to PK using a direct response inhibitory sigmoid model and an indirect response turnover model, respectively. The antitumor activity of alisertib dosed orally for 21 days with different dose levels and schedules was evaluated. RESULTS: The PK/PD models showed a fast, sustained response for AS after alisertib administration, whereas MI exhibited a slow, transient response. The PK/efficacy relationship for alisertib in HCT-116 xenografts closely corresponds to the PK/PD relationship for the PD markers, with all three IC50s in close agreement (303, 270, and 280 nM, respectively). CONCLUSION: The PK/PD and PK/efficacy models show that both AS and MI are equally relevant as mechanism-based PD markers to capture drug activity. However, of the two PD markers, the fast, sustained response of AS makes it the only clinically viable PD marker for defining a dose-response relationship, as its maximal effect can be captured from a wider time window with a single PD sampling; while the window to capture dose-related MI response is narrower.