Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting

Pharmaceutical Research - Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung...     

Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non–Small Cell Lung Cancer

The rapidly expanding repertoire of immune checkpoint inhibitors (ICIs) now includes two agents, pembrolizumab and atezolizumab, approved for first-line treatment of advanced non–small cell lung cancer (aNSCLC) as monotherapy or as part of chemoimmunotherapy. This review summarizes the clinical evidence supporting these indications, with a focus on strategies to optimize patient outcomes. These strategies include patient and tumor factors, adverse-effect profiles, pharmacokinetic and pharmacodynamic drug interactions, and quality of life and cost-effectiveness considerations. We performed a systematic literature search of the PubMed, Scopus, and Google Scholar databases, as well as a search of the conference proceedings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research (through August 31, 2019). The addition of ICIs to conventional chemotherapy as first-line treatment against aNSCLC is now part of the standard of care options. However, even though ICIs may be cost-effective in patients with aNSCLC, high drug and other associated costs can still be a barrier to treatment for patients. Moreover, the adverse-effect profiles of ICIs differ significantly from conventional chemotherapy, and some immune-related adverse effects may have a lasting impact on quality of life. Therefore, in adhering to a patient-centered model of care, clinicians should be mindful of patient- and treatment-specific factors when considering therapeutic options for patients with aNSCLC. Although the role of the immune system in cancer progression and regression has not been fully elucidated, the full clinical potential of immunotherapeutics in the treatment of cancer likely remains to be unleashed.     

Physiologically Based Modeling of the Pharmacokinetics of “Catch-and-Release” Anti-Carcinoembryonic Antigen Monoclonal Antibodies in Colorectal Cancer Xenograft Mouse Models

Engineered monoclonal antibodies (mAbs) with pH-sensitive target release, or “catch-and-release” (CAR) binding, have shown promise in decreasing the extent of target-mediated mAb elimination, increasing mAb exposure, and increasing dose potency. This study developed a mechanistic physiologically based pharmacokinetic (PBPK) model to evaluate the effects of pH-sensitive CAR target binding on the disposition of anti-carcinoembryonic antigen (CEA) mAbs in mouse models of colorectal cancer. The PBPK model was qualified by comparing model-predicted plasma concentration-time data with data observed in tumor-bearing mice following the administration of T84.66, a “standard” anti-CEA mAb that demonstrates strong binding at pH 7.4 and 5.5. Further simulations evaluated the effects CAR pH-dependent binding, with decreasing CEA affinity with decreasing pH, on anti-CEA mAb plasma pharmacokinetics. Simulated data were compared with data observed for a novel CAR mAb, 10H6. The PBPK model provided precise parameter estimates, and excellent data characterization (median prediction error 18.4%) following fitting to T84.66 data. Simulations well predicted 10H6 data (median prediction error 21.4%). Sensitivity analyses demonstrated that key determinants of the disposition of CAR mAbs include the following: antigen binding affinity, the rate constant of mAb-CEA dissociation in acidified endosomes, antigen concentration, and the tumor vasculature reflection coefficient.     

Pharmacokinetic–Pharmacodynamic Modeling of Tolmetin Antinociceptive Effect in the Rat Using an Indirect Response Model: A Population Approach

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC₅₀ of 9.22 g/ml. This IC₅₀ is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 g/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.     

Elderly Subset Analysis of Randomized Phase?III Study Comparing Pemetrexed Plus Carboplatin with Docetaxel Plus Carboplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Background

Many physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.

Objective

This was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).

Methods

Data from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.

Results

The ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3–4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23–0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20–0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32–0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34–0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3–4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.

Conclusion

The benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk–benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.     

Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods.     

Application of Box-Behnken Design in the Preparation,Optimization, and In Vitro Evaluation of Self-Assembly–Based Tamoxifen- and Doxorubicin-Loaded and Dual Drug–Loaded Niosomes for Combinatorial Breast Cancer Treatment

This study was developed with the objective to prepare self-assembled niosomes to support sufficient entrapment and sustained drug release of the drugs having different solubility and mechanisms. In the current work, Tamoxifen- and Doxorubicin-loaded niosomes were prepared for combinatorial breast cancer treatment with statistical optimization by Box-Behnken experimental design. Atomic force microscopy revealed a spherical shape morphology of the niosomes. The entrapment efficiencies for the drugs were found to be 74.3% and 72.7% for Tamoxifen and Doxorubicin, respectively. The drug release experiments at different pH values displayed a sustained release up to 3 days. Fourier transform infrared spectroscopy and differential scanning calorimetry showed a robust drug-excipient compatibility. The niosomes were stable over a period of 6 months with no significant changes. In vitro cytotoxicity studies on MCF-7 cell line showed a 15-fold improvement (0.01 μg per mL) and a better synergistic effect of the niosomes in comparison to the free drug combination (0.15 μg per mL). Moreover, the nanocarrier uptake studies by fluorescence microscopy and flow cytometry showed a good distribution and greater uptake of the niosomes throughout the cells. These results suggest a profound therapeutic application of the niosomes for a combinatorial breast cancer treatment.