An audit of therapeutic drug monitoring services of anticonvulsants at a tertiary care hospital in India.

BACKGROUND: Therapeutic drug monitoring (TDM) is an important adjunct to the treatment of epilepsy. However, few studies have actually correlated plasma levels of antiepileptic drugs (AEDs) with treatment response. The present audit aimed to study (i) the association between seizure control and number of AEDs, plasma AED concentration, and concomitant use of antitubercular drugs; (ii) the pattern of indications for TDM requisitions; and (iii) the association between referral for toxicity and plasma AED concentration. METHODS: This observational and retrospective study was carried out to analyze the TDM data of patients referred between January 2008 and December 2011. As per the International League Against Epilepsy Task Force 2009, patients were categorized into responders and nonresponders. Plasma AED levels were interpreted as below, within, and above the reference range. RESULTS: Of 3206 TDM requisitions, 67% were monotherapy and 33% were 2 or more AEDs. Only 8% were responders as against 92% nonresponders. Of 95 patients on concomitant antituberculosis treatment, 72 were nonresponders, with odds ratio (95% confidence interval) 3.71 [2.19 to 6.23]. Breakthrough seizure (37%) was the most common indication followed by suspected toxicity and routine monitoring in 22% each and suspected nonadherence in 11% of the total requests. In 52% of patients, plasma levels were below the reference range, and they were equally distributed amongst responders and nonresponders. Among patients referred for suspected phenytoin toxicity, only 59% (50.6 to 67.8) had plasma concentrations above the reference range. CONCLUSIONS: TDM continues to remain an important tool to support dose individualization when the patient is receiving multiple AEDs or other drugs such as antitubercular medicines, to assess compliance, and to monitor and treat toxicity.

Association of CYP2C9 polymorphisms with phenytoin toxicity in Indian patients.

BACKGROUND: Genetic polymorphisms of CYP2C9 can lead to wide inter-individual variations in drug metabolism. Decreased metabolism leads to higher plasma levels, causing adverse drug reactions (ADRs). Polymorphic alleles CYP2C9 FNx01 2 and CYP2C9 FNx01 3 occur in the Indian population and this may serve as the basis for using genotyping as a tool to predict phenytoin toxicity. AIMS: To evaluate the association between the presence of polymorphic alleles CYP2C9 FNx01 2 and FNx013 and phenytoin toxicity in Indian patients with epilepsy. SETTINGS AND DESIGN: A case-control study with cases defined as those who had plasma phenytoin concentrations above 20 µg/ml. MATERIALS AND METHODS: The study population included 259 patients with epilepsy on phenytoin. Phenotyping was done using High Performance Liquid Chromatography. Those with plasma phenytoin levels above 20 µg/ml were taken as cases and the rest as controls. Genotyping was done by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism. STATISTICS: Numerical data between groups was compared using unpaired-'t' test. Between-group comparison of categorical data was done using Chi square for trend with crude odds ratio (OR). Adjusted OR was calculated using binary logistic regression. RESULTS: There were 40 cases and 219 controls. Mean phenytoin dosage between groups was not statistically significant. Of the 40 cases, 25 (62.5%) cases had wild alleles versus 178 (81.3%) controls. We found a significant association between polymorphic alleles CYP2C9 FNx01 2 and FNx013 and toxic phenytoin levels. After adjusting for age, sex and dose, a significant association between polymorphic alleles and phenytoin toxicity was still found. CONCLUSIONS: This study shows significant association between polymorphic alleles and phenytoin toxicity in this study population. However, until technology for genotyping becomes cost-effective, we would recommend Therapeutic Drug Monitoring to guide dosing.

Safety of apixaban in Indian patients undergoing elective total knee replacement or total hip replacement surgery: A multi-center, phase-IV study.

BACKGROUND: Venous thromboembolism is a significant source of morbidity and mortality following total hip replacement and total knee replacement. Apixaban has been proven to be efficacious without increased risk of bleeding in phase-III trials in patients undergoing total knee replacement and total hip replacement. Due to paucity of data on safety of apixaban in Indian patients, this phase-IV study was conducted to evaluate safety of apixaban in patients undergoing total knee replacement and total hip replacement. METHODS: In this non-comparative phase-IV clinical trial, patients undergoing elective total knee replacement or total hip replacement surgery, or a revision of at least one component of total knee replacement or total hip replacement, were enrolled. The eligible patients were given the approved dosage of apixaban 12 to 24 h after completing the skin wound closure. The primary safety outcome was the composite of the International Society on Thrombosis and Haemostasis-defined major bleeding and clinically relevant non-major bleeding events at the end of the treatment. The secondary efficacy endpoint was the composite of venous thromboembolism/all-cause death at the end of the treatment. RESULTS: A total of 498 patients received apixaban prophylaxis therapy. Six (1.2%) bleeding adverse events were observed during the treatment period. Only one bleeding event was adjudicated as an International Society on Thrombosis and Haemostasis-defined clinically relevant non-major bleeding event (moderate severity). There were no fatal bleeding events and no deaths following the treatment. One venous thromboembolism event, that is, symptomatic distal left leg DVT, was reported in a total knee replacement patient and was adjudicated during the treatment period. CONCLUSION: Apixaban demonstrated a favorable safety profile for venous thromboembolism prevention in Indian patients undergoing total knee replacement or total hip replacement.

A study of agreement between the Naranjo algorithm and WHO-UMC criteria for causality assessment of adverse drug reactions.

OBJECTIVES: Reliability and usefulness of various adverse drug reaction (ADR) causality assessment scales have not been fully explored. There is no universally accepted method for causality grading of ADRs. In the present study we assessed agreement between the two widely used causality assessment scales, that is, the World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria and the Naranjo algorithm. MATERIALS AND METHODS: The same observer assessed all ADRs (n = 913) collected between January 2010 and December 2012 using the WHO-UMC criteria and Naranjo algorithm at a tertiary care hospital in India. We found that the most frequently assigned causality category was "possible" with both the scales. RESULTS: A disagreement in the causality assessment was found in 45 (4.9%) cases reflecting "poor" agreement between the two scales (Kappa statistic with 95% confidence interval = 0.143 [0.018, 0.268]). The mean time taken to assess causality of the ADR using the WHO-UMC criteria was shorter than that by the Naranjo algorithm. CONCLUSION: This study showed that there is a poor agreement between the WHO-UMC criteria and Naranjo algorithm with the former being less time-consuming.

Establishing institutional ethics committees: challenges and solutions - a review of the literature.

This review of the literature was conducted to identify the challenges faced while establishing institutional ethics committees (IECs) as well as to suggest some solutions. The search of the literature was carried out with the help of the PubMed search engine, using "research ethics committees" (MeSH] and "India" (MeSH]) as the key words for articles published between 2004 and 2012. We found 31 articles related to the topic, and the most common challenge mentioned was inappropriate functioning of IECs (n=17), followed by inappropriate structure (n=14). The authors identified many challenges related to the lack of oversight by regulatory bodies (n=14) as well as issues pertaining to the ethical training of IEC members and investigators (n=13). It is evident from the multitude of papers on the issue that the challenges related to the constitution and functioning of IECs must be given the attention they deserve to ensure that research participants in India are better protected.

Survey of ethics committee protocol approval letters: compliance with Schedule Y/ICMR guidelines 2006.

A study was carried out to determine the extent to which ECs comply with format requirements given in guidelines and regulations. ECs were sent a written communication requesting them to permit investigators to study their approval letter for compliance with the ICMR Guidelines and Schedule Y using a pre-designed proforma. Of the 60 ECs approached, only 20 agreed to participate. Legal experts and social scientists were not present at the approval meetings of most of the ECs. Only 7 ECs had a quorum according to Schedule Y Several ECs did not state whether documents such as the clinical trial agreement and insurance policy were reviewed. Delays in sending approval letters could be shortened with efficacious operating of ECs. There is a need to train EC members and create a better awareness of regulatory requirements. There is also a need to evolve a mechanism to monitor EC functioning.