Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.

Background And Objective: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties.

Human Data on Pharmacokinetic Interactions of Cannabinoids: A Narrative Review.

Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications.

Therapeutic advantages of the combined use of closantel and moxidectin in lambs parasitized with resistant gastrointestinal nematodes.

The serious widespread development of nematode resistance has motivated the use of combined anthelmintic formulations. However, the advantages/disadvantages of the combined use of anthelmintics require further scientific characterization. The goals of the current trial were a) to characterize the pharmacokinetics of closantel (CLO) and moxidectin (MXD) administered both subcutaneously (sc) and orally either separately or co-administered (CLO + MXD) to lambs; b) to compare the nematodicidal activity of both molecules given individually or co-administered to lambs infected with resistant nematodes.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial β-oxidation by facilitation of its entrance via the carnitine shuttle.

Tissue Drug Concentration.

Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues.

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy.

Drug-resistant epilepsy has been explained by different mechanisms. The most accepted one involves overexpression of multidrug transporters proteins at the blood brain barrier and brain metabolizing enzymes. This hypothesis is one of the main pharmacokinetic reasons that lead to the lack of response of some antiseizure drug substrates of these transporters and enzymes due to their limited entrance into the brain and limited stay at the sites of actions.

Development of a Population Pharmacokinetic Model for Cyclosporine from Therapeutic Drug Monitoring Data.

Aim: To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. . A total of 53 patients under treatment with CsA were included.

Enteric reabsorption processes and their impact on drug pharmacokinetics.

Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR).

Clinical Pharmacokinetics of Cannabinoids and Potential Drug-Drug Interactions.

Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes.

Pharmacokinetics of Subcutaneous Levetiracetam in Palliative Care Patients.

Seizure control is challenging in the palliative care setting. Subcutaneous (SC) levetiracetam (LEV) is currently an off-label route of administration and effectiveness, tolerability, and pharmacokinetics studies for this route are scarce. This prospective study aimed at evaluating effectiveness and tolerability of SC LEV as well as characterizing its pharmacokinetics.

Potential Therapeutic Role of Carnitine and Acetylcarnitine in Neurological Disorders.

Background: Current therapy of neurological disorders has several limitations. Although a high number of drugs are clinically available, several subjects do not achieve full symptomatic remission. In recent years, there has been an increasing interest in the therapeutic potential of L-carnitine (LCAR) and acetyl-L-carnitine (ALCAR) because of the multiplicity of actions they exert in energy metabolism, as antioxidants, neuromodulators and neuroprotectors.

Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia.

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring.

Sex-by-formulation interaction in bioequivalence studies: the importance of formulations and experimental conditions.

In a recently published investigation, the authors argued against the likelihood of sex-based subject-by-formulation interactions in bioequivalence studies, i.e. male and female subjects exhibiting different discriminatory potential to detect bioavailability differences between formulations.

Lamotrigine-Valproic Acid Interaction Leading to Stevens-Johnson Syndrome.

Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens-Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA).

Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products.

Bioequivalence implementation in developing countries where a high proportion of similar drug products are being marketed has found several obstacles, impeding regulatory agencies to move forward with this policy. Biopharmaceutical quality of these products, several of which are massively prescribed, remains unknown. In this context, an in vitro-in silico-in vivo approach is proposed as a mean to screen product performance and target specific formulations for bioequivalence assessment.

Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects.

Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX).

L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report.

Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination.

Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy.

Background: Identified the polymorphisms of CYP2D6, CYP2C9, CYP2C19 and CYP3A4, within a rigorously selected population of pediatric patients with drug-resistant epilepsy.

Method: The genomic DNA of 23 drug-resistant epilepsy patients and 7 patients with good responses were analyzed. Ten exons in these four genes were genotyped, and the drug concentrations in saliva and plasma were determined.

Sex Effect on Average Bioequivalence.

Purpose: Generic formulations are by far the most prescribed drugs. This scenario is highly beneficial for society because medication expenses are significantly reduced after expiration of the exclusivity period conceded to the branded name drug. Correspondingly, these formulations must be adequately evaluated to avoid drug inefficacy and toxicity in the overall patient population.

Current State and Future Perspectives in QSAR Models to Predict Blood- Brain Barrier Penetration in Central Nervous System Drug R&D.

The Blood-Brain Barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu).

Sex and Food Influence on Intestinal Absorption of Ketoprofen Gastroresistant Formulation.

Sixteen healthy volunteers (8 women and 8 men) participated in a 2-period, 2-treatment crossover study. A delayed-release gastroresistant formulation of ketoprofen was administered under fasting and fed conditions. Cmax , AUC, Cmax /AUC, and kel obtained after food coadministration did not differ from those calculated under fasting administration.

Complete dataset for 2-treatment, 2-sequence, 2-period efavirenz bioequivalence study conducted with nightly dosing.

The efavirenz pharmacokinetic raw data presented in this article was obtained in an average bioequivalence study between a local brand and Stocrin (Merck Sharp & Dohme, purchased from Australia, batch H009175, expiration date November 2013). Dose was administered at night (9:00 p.m.

Carnitine and/or Acetylcarnitine Deficiency as a Cause of Higher Levels of Ammonia.

Blood carnitine and/or acetylcarnitine deficiencies are postulated in the literature as possible causes of higher ammonia levels. The aim of this study was to investigate if the use of valproic acid, the age of the patients, or certain central nervous system pathologies can cause carnitine and/or acetylcarnitine deficiency leading to increased ammonia levels. Three groups of patients were studied: (A) epileptic under phenytoin monotherapy (n = 31); (B) with bipolar disorder under valproic acid treatment (n = 28); (C) elderly (n = 41).