Studies on the Mechanism of Absorption of Depot Neuroleptics: Fluphenazine Decanoate in Sesame oil

Purpose. The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. Methods. A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. Results. After intravenous FLU-D, the pharmacokinetics of the prodrug (mean ± SD) were as follows: Clearance (CL) 42.9 ± 6.3 L/h; terminal half-life (t_1/2) 3.5 ± 0.8 h; volume of distribution (Vd) 216 ± 61 L. The fractional availability of FLU was 1.0 ± 0.2. After intravenous FLU, the volume of distribution of FLU (51 ± 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t_1/2 of FLU was 9.7 ± 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t_1/2 was only 7.7 ± 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. Conclusions. The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.     

Individual bioequivalence-has its time come?

A forthcoming draft Guidance of the Food and Drug Administration is expected to replace the current framework for the assessment of bioequivalence, based on the comparison of average kinetic responses, with a very different approach, the evaluation of individual bioequivalence. It emphasizes the estimation of intraindividual variances of the contrasted drug products as well as of the subject-formulation interaction, and requires the conduct of 4- (or 3-) period crossover bioequivalence trials. In order to facilitate the discussion of the draft Guidance and of the new approach, the underlying rationale, principles and procedures are described. Following this, various open questions are raised. It is suggested that their resolution should be carefully and widely discussed, and that more research and experience is needed before the possible implementation of the new approach.     

Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium

Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8.     

Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine

Quinidine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48?h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r _s?=??0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (α?=?0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Mefloquine Hydrochloride

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.     

Subnanogram quantitation of chlorpheniramine in plasma by a new radioimmunoassay and comparison with a liquid chromatographic method

A new radioimmunoassay (RIA) procedure for the quantitation of chlorpheniramine in plasma is described. The assay allows the determination of chlorpheniramine levels up to 96 h after oral administration of a single 4-mg tablet to healthy volunteers. This procedure was sensitive to a 156-pg/mL plasma concentration when a 100-microL plasma sample was used. The mean coefficient of variation over the linear range of the assay from 0.156 to 20 ng/mL was 3.79%. The specificity of the assay was investigated, and the antisera showed 7% cross-reactivity with the N,N-didemethyl analogue and 17% cross-reactivity with the N-demethyl analogue. This high degree of specificity was also evident from the findings that the plasma concentrations determined by this newly described RIA procedure in samples of two healthy male volunteers who were administered 4 mg of chlorpheniramine maleate orally gave a strong correlation (r2 = 0.88) with values obtained by an HPLC-UV procedure. The antiserum cross-reacted 100% with brompheniramine and, thus, can be used for its analysis in plasma. The described RIA procedure is precise, simple, and capable of handling a large number of plasma samples with a minimal turnaround time.     

Methoxyphenamine O-demethylase and 5-hydroxylase: a GLC-ECD assay to study their activities and their inhibition by debrisoquine and sparteine

A GLC-ECD method is described for the determination of the O-desmethyl, N-desmethyl and aromatic 5-hydroxy metabolites of methoxyphenamine in liver homogenates. The O-desmethyl and 5-hydroxy metabolites are deficient in poor metabolizers of debrisoquine and sparteine and the Dark Agouti rat model of this human phenotype. The present analytical method can be useful in determining methoxyphenamine O-demethylase and 5-hydroxylase activities as well as identifying those substrates which inhibit these and are worthy of further study.     

Clinical Characteristics and Treatment Outcome of Central Nervous System Nocardiosis: A Systematic Review of Reported Cases

BackgroundThe clinical spectrum of systemic nocardiosis encompasses pulmonary and disseminated disease. Central nervous system (CNS) involvement is an important feature of disseminated disease with significant mortality and high relapse rate, especially in those with suppressed cell-mediated immunity. This systematic review aimed to evaluate the epidemiology, clinical features, diagnosis, therapeutic interventions, and outcome in patients with CNS nocardiosis.MethodsA literature search was performed in major databases (PubMed, Google Scholar, and Scopus) by using distinct keywords: “CNS disease,” “Nocardia,” “meningitis,” “brain abscess,” “disseminated disease,” and “Cotrimoxazole.” We included all patients ≥18 years with CNS nocardiosis reported between January 2000 and December 2020.ResultsA total of 129 papers were included in the final analysis. The mean age of patients was 55 ± 16 years, and the majority were male (70.8%). Nocardia farcinica was the commonest species (39.6%), followed by Nocardia nova (5.9%). Thirty-four percent of the patients were found to be immunocompetent. Corticosteroid use was the most common predisposing factor (55.8%). Among neuroimaging findings, brain abscess was most common (86.9%), followed by leptomeningeal enhancement (12.1%). The overall case-fatality rate in CNS disease was 22.8%. On multivariate analysis, patients who underwent surgery (OR 2.4, 95% CI 0.99–4.11, p value 0.046) had better survival than those treated with antimicrobial therapy alone. Immunodeficient state (OR 0.32, 95% CI 0.15–0.90, p value 0.019) was independently associated with poor outcome.ConclusionCNS nocardiosis carries significant mortality, especially in immunodeficient patients. We advocate the use of surgery combined with antimicrobials to improve clinical outcome.     

EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII)

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in tumors of adenocarcinoma (ADC) histology (NSCLC/ADC). Robust data exist regarding the prevalence of EGFR mutations in Western and Asian patients with NSCLC/ADC, yet there is a lack of data for patients of other ethnicities. This review collated available data with the aim of creating a complete, global picture of EGFR mutation frequency in patients with NSCLC/ADC by ethnicity. Worldwide literature reporting EGFR mutation frequency in patients with NSCLC/ADC was reviewed, to create a map of the world populated with EGFR mutation frequency by country (a ‘global EGFR mutMap’). A total of 151 worldwide studies (n=33162 patients with NSCLC/ADC, of which 9749 patients had EGFR mutation-positive NSCLC/ADC) were included. There was substantial variation in EGFR mutation frequency between studies, even when grouped by geographic region or individual country. As expected, the Asia-Pacific NSCLC/ADC subgroup had the highest EGFR mutation frequency (47% [5958/12819; 87 studies; range 20%-76%]) and the lowest EGFR mutation frequency occurred in the Oceania NSCLC/ADC subgroup (12% [69/570; 4 studies; range 7%-36%]); however, comparisons between regions were limited due to the varying sizes of the patient populations studied. In all regional (geographic) subgroups where data were available, EGFR mutation frequency in NSCLC/ADC was higher in women compared with men, and in never-compared with ever-smokers. This review provides the foundation for a global map of EGFR mutation frequency in patients with NSCLC/ADC. The substantial lack of data from several large geographic regions of the world, notably Africa, the Middle East, Central Asia, and Central and South America, highlights a potential lack of routine mutation testing and the need for further investigations in these regions.