Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

Optimising inhaler technique in chronic obstructive pulmonary disease: a complex issue.

Inhaled therapies play a central role in the management of chronic obstructive pulmonary disease (COPD); however, studies indicate that many patients do not use their inhaled medication as directed, resulting in decreased medication delivery and suboptimal disease control. Key factors that should be considered when evaluating whether patients are achieving optimal outcomes with inhaled therapies are: if patients are using a correct inhalation technique; if patients have adequate dexterity to use the prescribed inhaler; if patients have sufficient inspiratory flow rate to achieve adequate lung deposition (for dry powder inhalers); and if the inhaler is accepted by the patient. There are many different types of dry powder inhalers available for COPD medications and their specific features can affect ease of use and suitability and acceptability for individual patients and patients' preferences.

A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG).

Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPDPIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPDAIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPDAIM varied from 4.4 to 5.0 µm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPDPIM was fixed at 5 µm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPDAIM/FPDPIM], expressed as a percentage, was contained in the predetermined 85-118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques.

Vector-control personnel's knowledge, perceptions and practices towards insecticides used for indoor residual spraying in Limpopo Province, South Africa.

BACKGROUND: Contradictory arguments regarding the benefits and harm of insecticides, especially DDT, have caused concerns in different societal circles, threatening to undermine the achievements of the indoor residual spraying (IRS) programme in South Africa. These concerns were exacerbated by the screening of a documentary on South African Broadcasting Corporation (SABC) Television with anti-DDT sentiments. Consequently, Limpopo Malaria Control Programme (LMCP) Management advocated for an investigation to determine the potential effect of such campaigns on vector-control personnel's knowledge and perceived effects of insecticides on human health, with a view to improving the educational materials designed for use in training vector-control personnel. METHODS: The study was a cross-sectional descriptive survey using a structured field-piloted questionnaire, administered to 233 randomly selected vector-control personnel. Ethical clearance was granted by the University of KwaZulu-Natal. Approval for the study was granted by the Department of Health, Limpopo. Participation in the study was voluntary and all respondents signed informed consent. Descriptive statistics were used to analyse the collected data. RESULTS: Most respondents (96.6%) had a positive perception of IRS as a method to control malaria. Despite their positive perception, 93.6% viewed IRS insecticides to be potentially harmful to the users. DDT was perceived to cause long-term reproductive and respiratory effects, whereas alpha-cypermethrin and deltamethrin were largely associated with skin irritation/itchiness and skin burn. Study participants were more worried about DDT's potential effects on their reproductive system, including poor sexual performance, decline in libido, miscarriage and bearing children with genetic defects. However, none reported personal experience of bearing a child with genetic defects or miscarriage.Most anti-insecticide messages, especially relating to DDT, emanated from sources external to the LMCP, mainly through radio (62%) and television (33.9%) and about 70% believed such messages. While most respondents preferred to work with a moderately itchy deltamethrin, DDT was admittedly the most effective insecticide. CONCLUSION: Vector-control personnel faced health and ethical dilemmas, in that, while they perceived insecticides used for IRS in Limpopo to be potentially harmful to the health of users, as purported through media, they also viewed IRS using insecticides to be effective in controlling malaria.

Towards the elimination of malaria in South Africa: a review of surveillance data in Mutale Municipality, Limpopo Province, 2005 to 2010.

BACKGROUND: South Africa has targeted to eliminate malaria by the year 2018. Constant monitoring of malaria morbidity and mortality trends in affected subpopulations is therefore crucial in guiding and refining control interventions. Mutale Municipality in Limpopo Province is one of the areas with the highest risk of malaria in the country. This paper describes trends in malaria incidence, case fatality and household indoor residual spraying (IRS) coverage in Mutale Municipality, during the period 2005 to 2010. METHODS: A retrospective descriptive analysis was conducted on malaria data routinely collected through the Limpopo provincial malaria information system between July 2005 and June 2010. Five malaria seasons were defined. Annualized malaria incidence rates, case fatality rates (CFR) and IRS coverage rates were calculated. RESULTS: Cumulatively, 4,663 malaria cases and 21 malaria deaths were reported in Mutale between July 2005 and June 2010. Investigation of likely origin of the malaria in 3,517 patients revealed that 6.6% were imported cases, mostly from neighbouring Zimbabwe (222/231). Malaria incidence rates fell from 13.6 cases per 1,000 person-years in the 2005-2006 season to 2.7 cases per 1,000 person-years in the 2009-2010 season. The mean malaria CFR was stable between 0.3 and 0.6% during the first four seasons, and increased sharply to 2.1% in the 2009-2010 season. The median age of the 21 malaria deaths was 34 years (range: 16 to 60 years). CFRs were 0% in children below 15 years and above 0.5% in patients more than 24 years old. Regular IRS achieved coverage above 80% in all five seasons. CONCLUSION: Malaria control interventions implemented in Mutale significantly reduced the incidence of malaria in the population. In order to accurately monitor progress towards the elimination goal, the malaria control programme should strengthen the reporting and capturing of the data in the provincial malaria information system; all patients diagnosed with malaria should be investigated to determine the likely source of the malaria, and malaria related deaths should be audited to improve case detection and management. Furthermore, the country should strengthen cross border malaria control collaborations in order to minimize malaria importation.

Permeation of Boswellia extract in the Caco-2 model and possible interactions of its constituents KBA and AKBA with OATP1B3 and MRP2.

Traditionally Boswellia serrata extract is used in the Indian Ayurvedic medicine for the treatment of inflammatory diseases. In 2002 the EMEA designated Boswellia an orphan drug status for the treatment of peritumoral oedema. Pharmacokinetic studies yielded low plasma concentrations of the active ingredients 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA). In continuation of the tests investigating the factors limiting bioavailability of boswellic acids, the present study examined the permeability of KBA and AKBA in human Caco-2 cell lines. In addition, the interaction of KBA and AKBA with the organic anion transporter OATP1B3 and the multi drug resistant proteins P-glycoprotein and MRP2 was evaluated using partly fluorescent-based assays. The permeability studies revealed poor permeability of AKBA and moderate absorption of KBA with a P(app) value of 1.69 x 10(-6) cm/s. Most of KBA and AKBA were found to be retained by the Caco-2 monolayer. Neither KBA nor AKBA could be identified as substrates of P-glycoprotein. However, both KBA and AKBA modulated the activity of OATP1B3 and MRP2, indicating that therapeutic relevant interactions with other anionic drugs may be expected. The results of the present study provide the first explanation for the pharmacokinetic properties of KBA and AKBA.

Metabolism of boswellic acids in vitro and in vivo.

Boswellia serrata resin dry extract is among the few herbal remedies designated with an orphan drug status for the treatment of peritumoral brain edema. In addition, boswellic acids (BAs), the main active ingredients of B. serrata extracts, have potent anti-inflammatory properties, and may represent promising agents for the treatment of inflammatory diseases. Pharmacokinetic studies, however, revealed poor bioavailability, especially of 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta-boswellic acid (AKBA), the most potent BAs. To address the question of whether BAs are extensively metabolized, we determined the metabolic stability of KBA and AKBA in vitro, investigated the in vitro metabolism of BAs, and compared the metabolic profiles of KBA and AKBA with those obtained in rats in vivo. In rat liver microsomes and hepatocytes as well as in human liver microsomes, we found that KBA but not AKBA undergoes extensive phase I metabolism. Oxidation to hydroxylated metabolites is the principal metabolic route. In vitro, KBA yielded metabolic profiles similar to those obtained in vivo in rat plasma and liver, whereas no metabolites of AKBA could be identified in vivo. Furthermore, AKBA is not deacetylated to KBA. This study indicates that the efficacy of B. serrata extract may be enhanced by increasing the bioavailability of AKBA.

The long-term effects of DDT exposure on semen, fertility, and sexual function of malaria vector-control workers in Limpopo Province, South Africa.

Hormonally active chemicals in the environment such as DDT have been associated with declining male reproductive health, especially semen quality. A cross-sectional study of 60 workers was performed near the Malaria Control Center (MCC) in Tzaneen, Limpopo Province, South Africa. Tests included a questionnaire (sexual function, fertility, and job history), a physical examination of the reproductive system, and semen analysis (produced via coitus interruptus or masturbation). Sperm count, density, and motility using the World Health Organization criteria and morphology using the strict Tygerberg criteria were determined. Serum o'p' and p'p' isomers of DDE, DDT, and DDD were measured. Forty-eight (81.0%) participants produced a semen sample, while all completed the questionnaires and physical examination. The mean sperm count was 93.8+/-130.3 million, and sperm density was 74.6+/-85.1 million/mL. The mean normal morphology score was 2.5+/-1.8% of subjects. Eighty-four percent of morphology scores were below either the WHO or the Tygerberg criteria, with the highest individual score being 6%. Self-perceived current problems with sexual function ranged between 10% and 20%. The most prevalent genital abnormality was abnormal testis disposition at 71%. There were few significant associations between DDT exposure measures (measured as years worked at MCC and serum DDT) and reproductive outcomes. p'p'-DDT was negatively associated with semen count (beta=-3.7+/-1.7; P=0.04; R2=0.05 adjusted for age, abstinence, physical abnormality, and fever in last 2 months). While the semen quality in the study was less than normal, no strong evidence for a DDT effect was found.

The hormonal effects of long-term DDT exposure on malaria vector-control workers in Limpopo Province, South Africa.

DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] compounds, used in many developing countries, including South Africa, for the control of malaria vectors, have been shown to be endocrine disruptors in vitro and in vivo. The study hypothesis was that male malaria vector-control workers highly exposed to DDT in the past should demonstrate clinically significant exposure-related anti-androgenic and/or estrogenic effects that should be reflected in abnormalities in reproductive hormone levels. A cross-sectional study of 50 workers from three camps situated near the Malaria Control Center (MCC) in Tzaneen was performed. Tests included blood sampling before and after a gonadotropin-releasing hormone (GnRH) challenge (100 microg). Serum o'p' and p'p' isomers of DDE, DDT, and DDD and basal and post-GnRH challenge hormone levels, including luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone-binding globulin, estradiol (E2), and inhibin, were measured. The mean number of years worked at the MCC was 15.8+/-7.8 years and the mean serum DDT was 94.3+/-57.1 microg/g of lipid. Mean baseline E2 levels (62.4+/-29.9 pg/mL) exceeded the laboratory reference range. Associations between DDT exposure measures (years worked at the MCC and DDT compounds) and hormonal outcomes were weak and inconsistent. The most important finding was a positive relationship of baseline E2 and baseline testosterone with DDT compounds, especially with p'p'-DDT and -DDD. The strongest association found, adjusted for age and SHBG, was between baseline estradiol and p'p'-DDT (beta=1.14+/-0.33 pg/mL/microg/ g lipid, P=0.001, R2=0.31, n=46). An overall anti-androgenic mechanism best explains the results, but with a number of inconsistencies. Associations might be due to chance, as multiple comparisons were made. The results therefore do not suggest an overt anti-androgenic or estrogenic effect of long-term DDT exposure on hormone levels, but correlations do exist in a manner that is not understood.