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. Ninety-five percent confidence intervals for fed/fasting geometric mean ratio of Cmax /AUC and AUC were 0.80-1.14 and 0.80-1.23, respectively. A significant difference (P < .01) was found between lag-time medians (T0 ), with a longer T0 after food intake (5.5 vs 2.5 hours). Also, a significant difference between the medians of Tmax was found (P < .01), being 7.0 hours after food coadministration and 4.0 hours under fasting administration, but this difference disappeared once T0 was subtracted from Tmax . Cmax /AUC, which is related to drug absorption rate, showed significant differences between sexes. Men showed higher (P =.006) Cmax /AUC means (0.468 ± 0.094 vs 0.361 ± 0.087 h(-1) . Tmax was also significantly different (P < .05), being 4.0 (3.0-5.0) hours for men and 8.0 (5.0-10.0) hours for women. In conclusion, men showed a faster intestinal absorption rate with earlier time-to-peak plasma concentration of ketoprofen. Food coadministration extended the gastric residence time of formulation but exerted no effect on its intestinal absorption pattern.

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.) two hours after food intake. Fourteen healthy subjects, 8 women and 6 men, completed the study. For each subject, 15 data points until 96 h post-administration are included. Subject demographic characteristics and sequences of administration are provided along with individual pharmacokinetic profiles of efavirenz obtained for both formulations after a single oral dose of 600 mg. This data provides information in support of the research article "Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets" [1].

Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets.

Although sex-related differences in gastrointestinal physiology have been vastly reported, its impact on drug oral bioavailability and bioequivalence (product discrimination) is often ignored. On this work results from an average bioequivalence study between tablets containing 600mg of the antiretroviral efavirenz (EFV), carried out with 14 healthy subjects (8 female and 6 men) in a randomized 2-period, 2-treatment crossover design, are analyzed from a sex-based approach. Sequences were balanced within each sex group. Considering all subjects, no differences were observed on EFV absorbed amount, as shown by the estimated 90CI of the AUC96 Test/Reference bioequivalence ratio (T/R): 0.950-1.05. However, results were not conclusive due to the 90CI for CMAX T/R was 0.743-1.07. Over this parameter, a significant sex-by-formulation interaction was detected: 90CI CMAX T/R was 0.838-1.36 in women and 0.540-0.920 in men; with a 52% relative difference between point estimates. Formulation differences were therefore evidenced only by male subjects. In vitro dissolution and disintegration tests for both products were carried out in two aqueous media: A) SLS 0.25% and B) HCl/KCl pH1.2. T/R results for dissolution efficiency and tablet disintegration times of formulations in both A and B media were highly correlated with CMAX T/R bioequivalence results observed in women and men respectively, showing that a dissimilar gastrointestinal environment between sexes affected EFV oral absorption. This work shows how sex-by-formulation interaction can affect bioequivalence conclusions. Sex effect on product discrimination should be specially disclosed in bioequivalence studies, mainly for drugs aimed to be given to both sexes.

Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects.

BACKGROUND AND OBJECTIVES: Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified-release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test). METHODS: Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC-UV chiral method. Mean concentration-time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration-time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate. RESULTS: Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition. CONCLUSIONS: R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration-time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes.

Notas de farmacología: estudios de disolución de medicamentos del sistema nervioso central / Pharmacology notes: drug dissolution studies of the central nervous system

El propósito de los estudios in vitro es comparar las características de liberación del principio activo contenido en una forma farmacéutica sólida oral mediante la cantidad, o porcentaje de la dosis, disuelta en función del tiempo en condiciones controladas y validadas. Se realizó una comparación de disolución in vitro de flunitrazepam (Rohypnol®, Somnidual® e Inervon®) y de lamotrigina (Lamictal® y Epilepax®). Para los perfiles de disolución de flunitrazepam, una de las marcas comerciales tuvo un perfil de disolución muy diferente a las otras dos marcas. Para el caso de lamotriginano existió diferencia para aquellos pH que se consideran fundamentales para la disolución del comprimido en el tracto gastrointestinal. Los resultados obtenidos de los estudios in vitro son simplemente orientadores, permiten tan solo guiar la puesta en marcha del ensayo de bioequivalencia entre el test evaluado in vitro y la referencia utilizada en el mismo ensayo. No obstante, estos resultados pueden constituirse en un elemento de apoyo a la presunción de bioinequivalencia como causa de un evento adverso (ineficacia o toxicidad) detectado en los programas de farmacovigilancia actualmente en marcha.

Sex- and smoke-related differences in gastrointestinal transit of cyclosporin A microemulsion capsules.

The aim of this work was to study the effect of the sex and the smoking status on the pharmacokinetics and the bioequivalence assessment of a branded and a generic cyclosporine A microemulsion formulation in soft-gelatin capsule. Sixteen healthy volunteers (eight women and eight men) participated in a CyA bioequivalence study, with nine of the volunteers being smokers. Sandimmun Neoral® (brand formulation; Reference) and Sigmasporin Microral® (generic formulation; Test) were administered under fasting conditions. Pharmacokinetic parameters were calculated through non compartmental analysis. Bioequivalence was declared based on the 90% confidence intervals (90% CI) for the T/R ratio of the geometric means for each parameter. In vitro determination of the capsules opening time was performed in simulated gastric fluid without enzyme with USP Apparatus 2. The extent of absorption was similar between both products for all subjects or each sex-group. The absorption rate was similar for both products when considering all subjects, whereas a significant difference in the TMAX between the two products was observed for the male subjects only, which relates to its slower capsule opening time observed in vitro (12.4 versus 6.0 min). No differences were observed in women that could relate to their slower gastric emptying. Differences in drug exposure were observed between smokers and non-smokers. Sex- and smoke-related differences in the gastrointestinal transit should be considered when the on-set time would be determinant for the treatment success of a drug.

Hyperammonemia associated with valproic acid concentrations.

Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing ß -oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

Experiencia Uruguaya en Atención Farmacéutica activa en la comunidad / Uruguayan experience in community-wide active pharmaceutical care

Objetivo: realizar una actividad de difusión a la población sobre el uso racional de medicamentos, mediante la inserción de los estudiantes en el equipo de salud y analizar los datos farmacoterapéuticos obtenidos de esta actividad educativa. Métodos: en la vía pública se instaló una carpa de Atención Farmacéutica durante tres días donde participaron químicos farmacéuticos y médicos, quienes impartieron charlas sobre diferentes temas de salud preponderantes en la población uruguaya. Asimismo, los alumnos de Atención Farmacéutica, como parte de su formación práctica, participaron de esta actividad mediante la realización de entrevistas a los transeúntes, llenado de fichas de perfiles farmacoterapéuticos y de consumo de plantas medicinales, elaboradas para este fin, y la entrega de folletos informativos. A partir de las fichas farmacoterapéuticas se desarrolló un trabajo de investigación. Resultados: los alumnos del curso participaron de forma activa en el llenado de las fichas farmacoterapéuticas y mantuvieron una comunicación fluida con los asistentes a la carpa y con los profesionales de la salud. Se completaron 117 fichas farmacoterapéuticas (90 mujeres y 27 hombres). El 60 por ciento de los entrevistados consumía plantas medicinales. Sesenta personas recibían cuatro o más especialidades farmacéuticas. Las drogas antihipertensivas resultaron las más utilizadas. Veintitrés personas presentaban hipotiroidismo y dos personas de este grupo recibían litio para trastorno bipolar. Entre el grupo de mujeres: 18 tomaban ansiolíticos, 12 antidepresivos, 7 hipnóticos y 2 antisicóticos. Diecinueve personas manifestaron tener colesterol alto y 14 recibían medicación. Catorce presentaban artrosis y 10 estaban en tratamiento con analgésicos. Nueve personas presentaban gastritis, grupo este con un alto consumo de café y mate. Seis mujeres mayores de 50 años, declararon tener osteoporosis y solo tres recibían medicación a base de calcio y vitamina D. Conclusiones: la experiencia tuvo aceptación por el público y muestra una vez más la necesidad de la población de una educación sanitaria responsable(AU)

Objective: to conduct a health promotion activity for the population on the rational use of drugs, in which students participate with the rest of the health team and to analyze pharmacotherapeutic data collected in this educational activity. Methods: a pharmaceutical care tent was put up on a public area for three days where physicians and pharmacists participated, giving talks on various prevailing health issues that affect the Uruguayan population. Also, a number of pharmaceutical care students, as part of their practical training, participated in this activity by interviewing passers-by, filling out forms of pharmacotherapeutic profiles and of consumption of herbal medicines and giving people some information leaflets. A research study was carried out from the data collected in these pharmacotherapeutic forms. Results: the students actively participated in filling out the pharmacotherapeutic profiles and keeping fluent communication with the audience and with health professionals. One hundred and seventeen pharmacotherapeutic forms were completed (90 women and 27 men). Sixty percent of the interviewed people consumed herbal medicines. Sixty people received four or more medicines. Antihypertensive drugs were the most commonly used. Twenty three people had hypothyroidism and two people in this group were treated with lithium for bipolar disorder. In the female group 18 took anxiolytics, 12 antidepressants, 7 hypnotic drugs and 2 antipsychotic drugs. Nineteen people reported high cholesterol condition and 14 of them took medication. Fourteen had osteoarthritis and 10 were under painkiller treatment. Nine people had gastritis and this group showed high consumption rates of coffee and mate. Six women over 50 years old reported having osteoporosis and only 3 of them took calcium-based medication and vitamin D. Conclusions: the experience was well-accepted by the public and once again, the need for responsible health education of the population was demonstrated(AU)