Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.This work was partially supported by the ISCIII (PI17/00940, RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) cofunded by FEDER and by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100)S

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of lifeThis project was partially supported by Fundación Española de Farmacia Hospitalaria “Convocatoria de ayudas de proyectos para grupos de trabajo de la SEFH 2021-2022”, Plan Galego de Saude Mental (SERGAS) and Axencia Galega Innovación (Grupos de Potencial Crecimiento IN607B2020/11). Bandín-Vilar E.: Mondelo-García C. and Fernández-Ferreiro A. are grateful to the Carlos III Health Institute for financing their personnel contracts: CM20/00135, JR20/00026 and JR18/00014S

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

Oral administration of camptothecin (Cm) 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. (C) 2014 Elsevier Masson SAS. All rights reserved.G.R.-B. acknowledges Instituto de Tecnologia Quimica for a scholarship; Consolider-Ingenio 2010 (proyecto MULTICAT), Sub-programa de Apoyo a Centros de Excelencia Severo Ochoa, and Agencia de Gestico, d'Ajuts Universiteris i de Recerca (2009 SGR 758, to S.S.) I.G.-A., V.M.-S., M.G.-A. and M. B. acknowledge financial support from the European Financial Commission (Red bioFarma DCI-ALA/19.09.01/10/21526/245-297/ALFA III (2010)). J.L.G.-G. acknowledges the financial support of the CIBERER (Biomedical Network Research Center for Rare Diseases) ISCIII.Rodríguez Berna, G.; Mangas Sanjuan, V.; Gonzalez Alvarez, M.; Gonzalez Álvarez, I.; Garcia Gimenez, JL.; Díaz Cabañas, MJ.; Bermejo, M.... (2014). A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability. European Journal of Medicinal Chemistry. 83:366-373. doi:10.1016/j.ejmech.2014.06.050S3663738

Influence of Inter- and Intra-Batch Variability on the Sample Size Required for Demonstration of Equivalent Microstructure of Semisolid Dosage Forms

Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar microstructure of the semisolid. This investigation shows that the minimum number of batches to be compared of each product is 3 and the minimum number of units per batch could be 6 in the case of low intra- and inter-batch variability. If the products are not identical, i.e., 2.5–5% differences that are expected due to differences in the manufacturing process or the suppliers of excipients, 12 units and 6 batches are needed. If intra- or inter-batch variability is larger than 10%, the number of batches and/or the number of units needs to be increased. As the interplay between inter- and intra-batch variability is complex, the sample size required for each combination of inter- and intra-batch variability and expected difference between products can be obtained in the attached tables

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 psoriasi

Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State—A Case Study

(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, Cτ, partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for Cmax, AUC0-t and AUC0-inf, in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (Cmax, AUC0-t and AUC0-inf) and additional (Cτ, pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC0-τ, Cmax,ss, and Cτ,ss) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration–time curves precluded to show equivalence for Cτ,ss in the simulated study at steady state. This failure to show equivalence at steady state was predicted by Cτ, pAUCs and HVD in the single-dose study. Cτ was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (Cmax, AUC0-t and AUC0-inf) are not enough to guarantee bioequivalence at steady state for prolonged-release products