Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10-1 mL/h/kg). A precursor-pool PK-PD model (kin = 6.1 × 10-3 mg/h, kp = 8.6 × 10-4 h-1 and kout = 2.7 × 10-2 h-1) with a parallel transit chain (k0 = 1.9 × 10-1 h-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 × 10-1 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

Mechanistic characterization of oscillatory patterns in unperturbed tumor growth dynamics: The interplay between cancer cells and components of tumor microenvironment.

Mathematical modeling of unperturbed and perturbed tumor growth dynamics (TGD) in preclinical experiments provides an opportunity to establish translational frameworks. The most commonly used unperturbed tumor growth models (i.e. linear, exponential, Gompertz and Simeoni) describe a monotonic increase and although they capture the mean trend of the data reasonably well, systematic model misspecifications can be identified. This represents an opportunity to investigate possible underlying mechanisms controlling tumor growth dynamics through a mathematical framework. The overall goal of this work is to develop a data-driven semi-mechanistic model describing non-monotonic tumor growth in untreated mice. For this purpose, longitudinal tumor volume profiles from different tumor types and cell lines were pooled together and analyzed using the population approach. After characterizing the oscillatory patterns (oscillator half-periods between 8-11 days) and confirming that they were systematically observed across the different preclinical experiments available (p<10-9), a tumor growth model was built including the interplay between resources (i.e. oxygen or nutrients), angiogenesis and cancer cells. The new structure, in addition to improving the model diagnostic compared to the previously used tumor growth models (i.e. AIC reduction of 71.48 and absence of autocorrelation in the residuals (p>0.05)), allows the evaluation of the different oncologic treatments in a mechanistic way. Drug effects can potentially, be included in relevant processes taking place during tumor growth. In brief, the new model, in addition to describing non-monotonic tumor growth and the interaction between biological factors of the tumor microenvironment, can be used to explore different drug scenarios in monotherapy or combination during preclinical drug development.

A physiologically based pharmacokinetic model for open acid and lactone forms of atorvastatin and metabolites to assess the drug-gene interaction with SLCO1B1 polymorphisms.

Atorvastatin is the most prescribed 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used to lower cardiovascular risk and constitutes one of the best-selling drugs world-wide. Several physiologically based pharmacokinetic (PBPK) models have been developed to assess its non-straightforward pharmacokinetics (PK) as well as that of its metabolites and have been only applied to assess drug-drug interactions (DDI). Here we present a full PBPK model for atorvastatin and its metabolites able to predict within a 2-fold error their PK after the administration of a solid oral dosage form containing the calcium salt of atorvastatin in single and multiple dosing schedules at 20, 40, and 80 mg and 10 mg dose levels, respectively. Internal validation with data from Phase 1 clinical trials as well as external validation in predicting clinically relevant DDIs consolidated model structure and parameterization. The model has been used to quantitatively assess the drug-gene interaction (DGI) between SLCO1B1 polymorphisms and atorvastatin exposure and revealed that patients with a reduced activity in hepatic uptake of atorvastatin are at increased risk of suffering muscle discomfort because of a 30% lower clearance (p < 0.01), leading to a 40% and 33% higher (p < 0.05) atorvastatin AUC and Cmax, respectively. These findings could explain the reported hazard ratio of 1.4 (95% CI: 1.1-1.7, p = 0.02) for suffering statin-induced myopathies and the treatment discontinuation among these patients (odds ratio 1.67, p = 0.0001) observed in the context of routine clinical care.

Impact of Pharmacokinetic and Pharmacodynamic Properties of Monoclonal Antibodies in the Management of Psoriasis.

The treatment of psoriasis has been revolutionized by the emergence of biological therapies. Monoclonal antibodies (mAb) generally have complex pharmacokinetic (PK) properties with nonlinear distribution and elimination. In recent years, several population pharmacokinetic/pharmacodynamic (PK/PD) models capable of describing different types of mAb have been published. This study aims to summarize the findings of a literature search about population PK/PD modeling and therapeutic drug monitoring (TDM) of mAb in psoriasis. A total of 22 articles corresponding to population PK/PD models of tumor necrosis factor (TNF)-α inhibitors (adalimumab and golimumab), interleukin (IL)-23 inhibitors (guselkumab, tildrakizumab, and risankizumab), IL-23/IL-12 inhibitor (ustekinumab), and IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) were collected. A summary of the clinical trials conducted so far in psoriasis was included, together with the current structural population PK and PD models. The most significant and clinical covariates were body weight (BW) and the presence of immunogenicity on clearance (CL). The lack of consensus on PK/PD relationships has prevented establishing an adequate dosage and, therefore, accentuates the need for TDM in psoriasis.

Quantitative assessment of the exposure-efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy.

AIMS: The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher-type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure-efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values. METHODS: A prospective follow-up, semi-experimental multi-centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty-five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S-MRI) observations were enrolled. RESULTS: A two concatenated compartment model with zero-order endogenous production and first-order distribution (CL1 = 3.85 × 10-1 L/d) and elimination (CL2 = 1.25 L/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (kT = 6.14 × 10-1 d-1 ) effect on CL1 was incorporated. The final exposure-efficacy model was a longitudinal logistic regression model with a first-order Markov element. An Emax function (EC50 = 15.73 U/L and Emax = 2.33) linked steady-state concentrations of GCase in leukocytes to the probability of transition across the different S-MRI stages. CONCLUSION: A population pharmacokinetic model successfully characterized the leukocyte activity-time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure-efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision-making regarding clinical response in bone and optimal dosing strategy.

Semi-Mechanistic Model for the Antitumor Response of a Combination Cocktail of Immuno-Modulators in Non-Inflamed (Cold) Tumors.

Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.

The Role of Mathematical Models in Immuno-Oncology: Challenges and Future Perspectives.

Immuno-oncology (IO) focuses on the ability of the immune system to detect and eliminate cancer cells. Since the approval of the first immune checkpoint inhibitor, immunotherapies have become a major player in oncology treatment and, in 2021, represented the highest number of approved drugs in the field. In spite of this, there is still a fraction of patients that do not respond to these therapies and develop resistance mechanisms. In this sense, mathematical models offer an opportunity to identify predictive biomarkers, optimal dosing schedules and rational combinations to maximize clinical response. This work aims to outline the main therapeutic targets in IO and to provide a description of the different mathematical approaches (top-down, middle-out, and bottom-up) integrating the cancer immunity cycle with immunotherapeutic agents in clinical scenarios. Among the different strategies, middle-out models, which combine both theoretical and evidence-based description of tumor growth and immunological cell-type dynamics, represent an optimal framework to evaluate new IO strategies.

Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations.

AIMS: The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP-binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. METHODS: Forty-eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5'-desoxi-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2 /24 h. Plasma measurements of CAP, 5'-DFUR and 5-FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration. RESULTS: The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5'-DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5-FU (184% increase for mutated rs2271862). System- (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10-2 ) and drug-related (slope [SLP] = 3.1 × 10-2 mL/mg). Co-administration of oxaliplatin resulted in a 2.84-fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively. CONCLUSIONS: The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2 /24 h in monotherapy and ≤1750 and ≤600 mg/m2 /24 h in combination with oxaliplatin, respectively, have been proposed.

EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma.

The use of daratumumab in combination with established regimens for the treatment of newly diagnosed multiple myeloma has recently been authorized by the European Medicines Agency based on results from three separate phase III randomized, active controlled, open-label studies that have confirmed enhanced efficacy and tolerability in both transplant-ineligible (MMY3008 and MMY3007) and transplant-eligible (MMY3006) patients, without compromising transplant ability. Trial MMY3008 showed an improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone; the median PFS had not been reached in the daratumumab arm and was 31.9 months in the control arm (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43-0.73; p < .0001). Trial MMY3007 showed an improvement in PFS when daratumumab was added to bortezomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone; PFS had not been reached in the daratumumab arm and was 18.1 months in the control arm (HR, 0.5; 95% CI, 0.38-0.65; p < .0001). In trial MMY3006, daratumumab added to bortezomib, thalidomide, and dexamethasone was compared with bortezomib, thalidomide, and dexamethasone as induction and consolidation treatment prior to autologous stem cell transplant. The stringent complete response rate at day 100 after transplant in the daratumumab group was 29% compared with 20% in the control group (odds ratio, 1.60; 1.21-2.12 95% CI; p = .0010). Overall adverse events were manageable, with an increased rate of neutropenia and infections in the daratumumab arms. Regulatory assessment of efficacy and safety results from trials MMY3006, MMY3007, and MMY3008 confirmed a positive benefit-risk ratio leading to an approval of the extensions of indication. IMPLICATIONS FOR PRACTICE: A set of extensions of indication was recently approved for daratumumab (Darzalex) in the setting of newly diagnosed multiple myeloma in combination with established regimens. Results of the MMY3006, MMY3007, and MMY3008 trials have shown enhanced efficacy and a favorable side effect profile of several daratumumab-based combinations in patients both ineligible and eligible for transplant, without compromising transplant ability. The combinations of daratumumab with either lenalidomide and low-dose dexamethasone or bortezomib, melphalan, and prednisone were approved for transplant-ineligible patients. The combination of daratumumab with bortezomib, thalidomide, and dexamethasone was approved for transplant-eligible patients. These combinations are expected to improve the survival outlook for patients with multiple myeloma, without an unacceptable risk of increase in adverse events, and updated information on progression-free survival and overall survival is expected from the above trials.

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice.

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

Systematic Modeling and Design Evaluation of Unperturbed Tumor Dynamics in Xenografts.

Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterize tumor growth dynamics and also optimize upcoming experiments. To the best of our knowledge, this is the first report where unperturbed growth of a large set of tumor cell lines (n = 28) has been systematically analyzed using a previously proposed model of nonlinear mixed effects (NLME). Exponential growth was identified as the governing mechanism in the majority of the cell lines, with constant rate values ranging from 0.0204 to 0.203 day-1 No common patterns could be observed across tumor types, highlighting the importance of combining information from different cell lines when evaluating drug activity. Overall, typical model parameters were precisely estimated using designs in which tumor size measurements were taken every 2 days. Moreover, reducing the number of measurements to twice per week, or even once per week for cell lines with low growth rates, showed little impact on parameter precision. However, a sample size of at least 50 mice is needed to accurately characterize parameter variability (i.e., relative S.E. values below 50%). This work illustrates the feasibility of systematically applying NLME models to characterize tumor growth in drug discovery and development, and constitutes a valuable source of data to optimize experimental designs by providing an a priori sampling window and minimizing the number of samples required.

Enhancing Oral Absorption of ß-Lapachone: Progress Till Date.

ß-Lapachone is a naphthoquinone with high and diverse biological activity. It is useful to treat several pathologies, in particular cancer due to its ability to induce selective apoptosis in tumoral cells. Despite its advantages, ß-lapachone's clinical applications are limited by its low solubility in biological fluids and its low specific distribution pattern. In the last decade various formulation strategies have been designed and developed in order to overcome these limitations and to make feasible its wide therapeutic use. The most relevant strategies for oral administration have been focused on the improvement of its solubility in order to increase ß-lapachone oral bioavailability. The use of cyclodextrins or the inclusion of the active substance in micelles and microparticles has demonstrated to be successful approaches. For topical and local application temperature-sensitive hydrogels have been developed to achieve high target concentrations. Polymeric micelles administrated subcutaneously have proved to be a long-lasting circulating system and to increase accumulation in tumor tissue making them an interesting formulation strategy.

Intestinal Permeability of ß-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures.

BACKGROUND AND OBJECTIVES: ß-Lapachone (ßLAP) is a promising, poorly soluble, antitumoral drug. ßLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on ßLAP intestinal permeability. The objectives of this work were to characterize ßLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of ßLAP. METHODS: Binary systems (physical mixtures and inclusion complexes) including ßLAP and CDs (ß-cyclodextrin: ßCD, random-methyl-ß-cyclodextrin: RMßCD and sulfobutylether-ß-cyclodextrin: SBEßCD) have been prepared and analysed by differential scanning calorimetry. ßLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. RESULTS: DSC results confirmed the formation of the inclusion complexes. ßLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. ßLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of ßLAP. Complexation with CDs does not reduce ßLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. CONCLUSIONS: The use of RMßCD or SBEßCD inclusion complexes could benefit ßLAP oral absorption by enhancing its solubility, dissolution rate and permeability.

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties.

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl6(2-) or PF6(-) respectively, display almost identical IC50 values in the sub-micromolar range (25-335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.

Semimechanistic cell-cycle type-based pharmacokinetic/pharmacodynamic model of chemotherapy-induced neutropenic effects of diflomotecan under different dosing schedules.

The current work integrates cell-cycle dynamics occurring in the bone marrow compartment as a key element in the structure of a semimechanistic pharmacokinetic/pharmacodynamic model for neutropenic effects, aiming to describe, with the same set of system- and drug-related parameters, longitudinal data of neutropenia gathered after the administration of the anticancer drug diflomotecan (9,10-difluoro-homocamptothecin) under different dosing schedules to patients (n = 111) with advanced solid tumors. To achieve such an objective, the general framework of the neutropenia models was expanded, including one additional physiologic process resembling cell cycle dynamics. The main assumptions of the proposed model are as follows: within the stem cell compartment, proliferative and quiescent cells coexist, and only cells in the proliferative condition are sensitive to drug effects and capable of following the maturation chain. Cell cycle dynamics were characterized by two new parameters, FProl (the fraction of proliferative [Prol] cells that enters into the maturation chain) and kcycle (first-order rate constant governing cell cycle dynamics within the stem cell compartment). Both model parameters were identifiable as indicated by the results from a bootstrap analysis, and their estimates were supported by date from the literature. The estimates of FProl and kcycle were 0.58 and 1.94 day(-1), respectively. The new model could properly describe the neutropenic effects of diflomotecan after very different dosing scenarios, and can be used to explore the potential impact of dosing schedule dependencies on neutropenia prediction.

A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability.

Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.

Semisynthesis, cytotoxic activity, and oral availability of new lipophilic 9-substituted camptothecin derivatives.

Despite that 9-substituted camptothecins are promising candidates in cancer therapy, the limited accessibility to this position has reduced the studies of these derivatives to a few standard modifications. We report herein a novel semisynthetic route based on the Tscherniac-Einhorn reaction to synthesize new lipophilic camptothecin derivatives with amidomethyl and imidomethyl substitutions in position 9. Compounds were evaluated for their antiproliferative activity, topoisomerase I inhibition, and oral availability. Preliminary data demonstrated that bulky imidomethyl modification is an appropriate lipophilic substitution for an effective oral administration relative to topotecan. In addition, this general procedure paves the way for obtaining new camptothecin derivatives.