Pharmacoepidemilogical, Socio-Economical and In-Vivo/In-Vitro Studies of Bisphosphonates Available in Pakistan

The evaluation and assessment of health care quality is receiving worldwide attention with medicines playing an important role in health care delivery to improve the health of patients. However in some countries, the costs of medicines can be up to 60% of total healthcare expenditure. Potential ways to address this include encouraging the prescribing of low-cost generics, especially with generics priced at 2% to 10% of pre-patent loss prices in some countries. In addition, enhancing adherence to the medicines prescribed to improve outcomes and reduce long term costs as well as increase physician familiarity with the medicines they prescribe and can be achieved through the use of formularies and prescribing guidance.Osteoporosis is a systemic skeletal illness illustrated by low Bone Mass Density (BMD) and micro architectural weakening of bone tissue. It is more common amongst people older than 50, with an estimated prevalence of up to one in four women and one in eight men, and is associated with considerable economic burden. It is estimated 75 million people worldwide are affected by osteoporosis. The prevalence of osteoporosis in Pakistan is also high. Estimates suggest 97% of women aged 75-84 years and 55% of women aged 45-54 years are prone to osteoporosis. Bisphosphonates are currently recommended as firstline treatment for patients with osteoporosis following a fracture to reduce the risk of subsequent fractures. Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone related diseases.Appropriate management of patients with osteoporosis and the quality of medicines is growing concerns in Pakistan. The first step to improve patient care is to understand current prescribing patterns and the rationale behind these.Vitamin D deficiency has been linked to the progression of osteoporosis and osteoporotic fractures arising from secondary hyperparathyroidism. The present study was conducted to assess utilisation patterns, prescribing behaviour, potential rationale among a range of medicines including bisphosphonatesusing appropriate methods, to conduct the invitro and in-vivo studies of oral formulations of Alendronate Sodium 70mg applying FDA and WHO guidelines and also assessment of serum vitamin D levels in asymptomatic populations. The studies were materialised through a questionnaire based, cross-sectional study conducted in both private and public health care facilities among five large cities of two Provinces of Pakistan (Punjab and Khyber Pakhtonkhwe – KPK) from January 2011 to December 2012. These cities and provinces representapproximately half the population of Pakistan. A questionnaire based cross-sectional study in both private and public health care facilities in Pakistan involving 438 physicians‘ and15824 prescriptions.Overall, a total 4815 people across all age groups and locations where subsequently included in the questionnaire and the taking of blood, i.e. selected through a convenience sampling technique. Their blood was subsequently analysed for serum vitamin D levels. The only exclusion criterion was that they were not currently suffering from any chronic diseases. The test principle was based on an Electro-chemiluminescence Immuno Assay (ECLIA). The body mass index (BMI) was calculated as weight (Kg) divided by height (m) squared.All the results were analysed using MS excel.The in-vitro study on Alendronate sodium was materialized through standardized pharmacopoeal specifications and in vivo study through an open-label randomized, 2- sequence, 2-period crossover study. These studies were carried out at National Institute of Health, Islamabad, Pakistan. Healthy Pakistani adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. Serial blood samples were collected and adverse events were monitored. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC(0-t), AUC(0-infinity), C(max), T(max), t(1/2), and the elimination constant (k(e)), were determined using non-compartmental analysis. There was adequate history taking and examinations in approximately half of the physicians surveyed, with prescribing typically taking into account issues such as disease severity (84% of respondents) and the socioeconomic status of patients (53%), which is encouraging. Prescribing of bisphosphonates was common certainly compared to medicines to treat cardiovascular diseases and diabetes. However concerns with the low use of generics, high rate of antibiotic prescribing, variable availability of medicines, medical representatives being a key source of information on medicines and typically a limited number of formularies. A high prevalence of vitamin D deficiency (VDD) was recorded irrespective of age, gender, race and geography in studied population. VDD was also seen among different income groups given the locations of the various cities and the sampling technique used, although others have shown higher prevalence in lower income groups. There was though a higher prevalence of VDD in women than men. Vitamin D deficiency was also seen irrespective of different sunshine levels seen in the five locations. Overall, only 8.6% of the population surveyed had normal levels of Vitamin D, 414/4815. The remainder, i.e. 91.4%, had mild to severe deficiencies; with 37.6% severely deficient, 28.6% moderately deficient and 25.1% were mildly deficient. The chemical assay, disintegration time and dissolution rate of all the brands tested were found within the pharmacopoeal specifications.The 90% CIs for the corresponding ratios of AUC(0-t), AUC(0-infinity) and C(max)for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study.Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC(0-t), AUC(0-infinity), and C(max) were found in this healthy Pakistani adult male population. There are considerable opportunities to improve the rational use of medicines in Pakistan including physician education, prescribing guidance and formularies. These should be coordinated among key stakeholder groups. There is also a need to ensure low prices for generics. Presently, there are no recommended guidelines to address VDD in Pakistan. However in view of the demonstrated prevalence of VDD in Pakistan across all age groups, it is suggested that policy makers develop such policies and include them in the forthcoming National health Plan aimed at combating for instance high priority non-communicable diseases including cardiovascular diseases and osteoporosis. Western countries have Vitamin D food fortification policies and it is suggested that Pakistan should immediately follow this example to reduce current high levels of VDD and their associated on patient well-being. The study will help the policy makers guide the various Government and private institutions to buy good quality generic alendronate sodium in order to cater the demands of patients who are suffering from osteoporosis. The Drug Regulatory Authority of Pakistan (DRAP) ensure bioequivalence studies for generic drugs and promote efficacious, high quality generics at a low price as compared to originator product.