Current Drug Metabolism - Volume 15, Issue 3, 2014

Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients. Most commonly used myeloablative and non-myeloablative conditioning regimens in children comprise alkylating agents, such as busulfan (BU) and cyclophosphamide. Inter-individual variability in the pharmacokinetics of BU can result in altered conditioning of the patient and therefore lead to relapse or rejection due to under exposures, or occurrence of toxicities due to over exposures. With the introduction of the intravenous formulation of BU, this variability has been reduced but still cannot be fully predicted. Inter and intra-individual variability of BU kinetics is more common in children compared to adults and toxicity of BU based regimens is still a concern. It has been hypothesized that some of this variability in BU pharmacokinetics and treatment outcomes, especially the toxicity, might be predicted by genetic variants of enzymes involved in the metabolism of BU. This review intends to summarize the studies performed to date on the pharmacokinetics and pharmacogenetics of BU based conditioning, specifically in relation to children.

Organic anion-transporting polypeptides (human OATPs; other species Oatps; gene family SLC21/SLCO) play important roles in drug absorption and distribution. In recent years, much information has been obtained on substrates that are transported by OATPs. Computer-based hydropathy analysis predicts that OATP family members share several structural features including twelve transmembrane domains (TMs), conserved cysteine residues at extracellular loop 5, glycosylation sites, PDZ binding domains as well as putative phosphorylation sites. Studies on transmembrane domains have identified several amino acids that are essential for substrate uptake; while mutation of the conserved cysteine residues and glycosylation sites resulted in mis-processing transporter proteins. The interaction with PDZ proteins and phosphorylation modification of OATPs, on the other hand, mainly regulate the trafficking of these transporters. Although progress has been made on revealing the critical domains of OATPs, information is still limited and more studies on these aspects are needed. A better understanding of the important structural domains of OATPs will shed light on future targeted drug design and a more in-depth analysis of inter-individual variability of drug disposition.

Biologics, including but not limited to monoclonal antibodies (mAbs), cytokines, growth factors, enzymes, hormones, vaccines, antibody fragments (e.g. Fabs), and antibody drug conjugates (ADCs), have a powerful clinical impact on the management of a wide variety of diseases. When compared to small molecules (SMs), they have different physicochemical properties and demonstrate unique and complex pharmacokinetic (PK) characteristics that are dependent on several factors such as net charge, neonatal Fc receptor [FcRn], Fcγ receptor [FcγR], glycosylation, PEGylation or aggregation. While PK principles are consistent, the underlying mechanisms that determine processes of absorption, distribution, metabolism, and excretion (ADME) of biologics are quite different from those of SMs. Furthermore, the immunogenicity, especially formation of anti-drug antibody (ADA) and cellular immune responses, may play an important role in their PK. Investigating the drug interaction (DI) potentials of biologics is inherently complicated, and the most well documented DI mechanism involves cytokine-mediated changes in drug-metabolizing enzymes. Population PK (Pop-PK) analyses have been successfully applied in assessing covariates in the disposition of biologics. The mechanism-based (target-mediated drug disposition [TMDD]) and physiologically based PK (PBPK) models are applied to predict PK characteristics of biologics. Developing a validated bioanalytical assay (mass assay, activity assay and immunogenicity assay) is critical in determining the PK properties of biologics. In this review, we will highlight the current knowledge, as well as the challenges around the PK-related issues in optimization of drug development and clinical practice of biologics.

Bioprecursor by definition is a type of prodrug that is designed to tackle pharmaceutical, pharmacokinetic or pharmacodynamic shortcomings of a drug that limit its clinical use. A retrometabolic approach is used to design bioprecursors which upon activation by either phase-I or phase-II metabolic enzymes result into an active metabolite. A bioprecursor differs from its active metabolite in many respects like physico-chemical, biological and toxicological aspects. Present review focuses on salient features of design and chemistry of bioprecursors and their active metabolites, activating metabolic enzymes/reactions, reported examples from literature and applications. We hope that this extensive compilation would open doors to bioprecursors and their active metabolites as very promising resources for the discovery of novel drugs possessing high efficacy with lower number and extent of adverse effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-thecounter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their efficacy and toxicity that allows dose adjustment. The individual response can however be altered by environmental and genetic pharmacokinetic and pharmacodynamic factors. This review summarizes the available pharmacogenetic data that explains part of the variability in response and occurrence of adverse drug reactions to NSAIDs treatment, with a thorough focus on CYP2C9, uridine diphosphate glucuronosyltransferases (UGTs) and cyclooxygenases (COX1 and COX2). Other polymorphisms that are currently being studied and could also explain the interindividual variability in the efficacy and safety of NSAIDs will also be considered.