Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first‐in‐class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target‐mediated drug disposition, leading to time‐ and concentration‐dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM

Basic pharmacodynamic models for agents that alter the lifespan distribution of natural cells

A new class of basic indirect pharmacodynamic models for agents that alter the loss of natural cells based on a lifespan concept are presented. The lifespan indirect response (LIDR) models assume that cells (R) are produced at a constant rate (k (in) ), survive during a certain duration T (R) , and finally are lost. The rate of cell loss is equal to the production rate but is delayed by T (R) . A therapeutic agent can increase or decrease the baseline cell lifespan to a new cell lifespan, T (D) , by temporally changing the proportion of cells belonging to the two modes of the lifespan distribution. Therefore, the change of lifespan at time t is described according to the Hill function, H(C(t)), with capacity (E (max) ) and sensitivity (EC (50)), and the pharmacokinetic function C(t). A one-compartment cell model was examined through simulations to describe the role of pharmacokinetics, pharmacodynamics and cell properties for the cases where the drug increases (T (D) > T (R) ) or decreases (T (D) < T (R) ) the cell lifespan. The area under the effect curve (AUCE) and explicit solutions of LIDR models for large doses were derived. The applicability of the model was further illustrated using the effects of recombinant human erythropoietin (rHuEPO) on reticulocytes. The cases of both stimulation of the proliferation of bone marrow progenitor cells and the increase of reticulocyte lifespans were used to describe mean data from healthy subjects who received single subcutaneous doses of rHuEPO ranging from 20 to 160 kIU. rHuEPO is about 4.5-fold less potent in increasing reticulocyte survival than in stimulating the precursor production. A maximum increase of 4.1 days in the mean reticulocyte lifespan was estimated and the effect duration on the lifespan distribution was dose dependent. LIDR models share similar properties with basic indirect response models describing drug stimulation or inhibition of the response loss rate with the exception of the presence of a lag time and a dose independent peak time. The current concept can be applied to describe the pharmacodynamic effects of agents affecting survival of hematopoietic cell populations yielding realistic physiological parameters

Modeling the effectiveness of paliperidone ER and olanzapine in schizophrenia: meta-analysis of 3 randomized, controlled clinical trials

The time course of Positive and Negative Syndrome Scale (PANSS) scores in adult schizophrenia patients was modeled, and the effectiveness of paliperidone extended-release tablets (paliperidone ER) and olanzapine was quantified. Data from 3 randomized, double-blind phase III studies were used. Patients received paliperidone ER (3, 6, 9, 12, or 15 mg), olanzapine 10 mg, or matched placebo once daily for 6 consecutive weeks. An indirect response model implemented using a nonlinear mixed effects approach described the time course of the PANSS. Deterioration rate was modeled as a function of baseline PANSS score, placebo, and drug effects, and the dropout effect. An exponential decrease of the placebo response was also implemented. Paliperidone ER and olanzapine treatment were characterized by a long-lasting drug effect (13%), with a larger but short-lasting placebo effect (40%) and a notable dropout rate. The covariate exploration failed to identify any clinically relevant factors. The non-parametric bootstrap analysis confirmed the acceptable precision of parameter estimates. The visual predictive check supported the model's adequacy to reproduce observed PANSS time courses. The population model describes the time course of PANSS scores in schizophrenia patients and is appropriate for use in clinical trial simulation activities

Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer.

To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events