AIMS 6 mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukaemia (ALL) and is conventionally available as 50 mg tablets. This study aimed to evaluate the bioequivalence of a new 6MP Powder for Oral Suspension (PFOS) intended for paediatric use. Additionally, a virtual study with the obtained data was planned for determining a dose of the PFOS that matches tablet exposures and to confirm optimal drug levels in pediatrics. METHODS An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy subjects. A population pharmacokinetic (PopPK) model was developed using the data to perform simulations with various PFOS doses and select a bioequivalent dose. To simulate 6MP and 6 thioguanine (6TGN) exposures in pediatrics, a literature model for paediatric ALL patients, and allometrically scaled PK parameters were utilised. RESULTS The 6MP PFOS had 47% higher bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to the 50mg tablets. The simulated 6TGN concentrations in virtual paediatric patients were between 114 and 703.6 pmol/8x108 RBCs, which was within the range of values reported in paediatric ALL studies. CONCLUSION The study demonstrates that 40 mg dose of 6MP PFOS 10 mg/mL has the same extent of absorption as the 50 mg tablet which can be precisely administered in pediatrics. The study also demonstrates the role of modelling and simulation to perform virtual bioequivalence and paediatric studies.

Over the last three to four decades, Therapeutic Drug Monitoring (TDM) has shaped itself as therapeutic drug management (TDM), an integral component of precision medicine. The practice of TDM is not extensive in India, despite being one of the fastest growing economies in the world. It is currently limited to a few academic medical centers and teaching hospitals. Apart from the immunosuppressive drugs, several other therapeutic areas like anticancer, antifungals, antibiotics and antitubercular have demonstrated great potential to improve the patient outcomes in the Indian settings. Factors like higher prevalence of nutritional deficiencies, tropical diseases, widespread use of alternative medicines, unalike pharmacogenomics, and sparse population specific data available on therapeutic ranges of several drugs, makes in the population of this subcontinent unique regarding the relevance of TDM. Despite the impact of TDM in clinical science and it’s widespread application, TDM has failed to receive the attention it deserves in India. This review intends to bring out a strength-weakness-opportunity and threats (SWOT) analysis for TDM in India so that appropriate steps for fostering growth of TDM could be envisioned. The need of the hour is creation of a cooperative group including all the stake holders like TDM professionals, clinicians and the government and devising a National Action Plan to strengthen TDM. Nodal TDM centres should be established and pilot programs should be rolled out for identifying the thrust areas for TDM in the country, capacity building and creating awareness to integrate TDM into mainstream clinical medicine.

High interindividual variability in pharmacokinetics coupled with concentration-effect relationship make sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with metastatic renal cell carcinoma (mRCC) was evaluated in this prospective observational study. Seventy patients with mRCC treated with sunitinib 50mg OD were enrolled. Total trough levels (TTL) of sunitinib and N-desethyl sunitinib were measured between days 10-14 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥3 toxicity was determined using receiver operating characteristic (ROC) curve. Threshold concentrations obtained from ROC analysis showed that TTL ≥60.75ng/mL was associated with higher response rates and TTL ≥82.3ng/mL was associated with higher incidence of grade ≥3 toxicity compared with lower exposures (31/34 versus 5/12, P=0.001 and 9/24 versus 4/36; P=0.024 respectively). More than 50% of patients in our cohort attained TTL outside the optimal range of 60.75-82.3 ng/mL demonstrating the feasibility of TDM.