1. The interspecies scaling approach to predict clearance in humans from animal data was tested for a wide variety of drugs. 2. Three different methods were utilized to generate plots to scale-up the clearance values: (i) method I, clearance versus body weight (simple allometric equation); (ii) method II, product of clearance and maximum life-span potential; (iii) method III, product of clearance and brain weight versus body weight. 3. The circumstances under which the three methods can be applied to predict clearance in humans were evaluated. 4. If the exponent lies between 0.55 to 0.7 then method I predicts clearance reasonably well. 5. If the exponent lies between 0.71 to 1.0 clearance can be predicted reasonably well by method II. 6. If the exponent is > 1.0 clearance can be predicted using method III.

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It should be recognized that children are not small adults, hence dosing in children should not be a 'small adult dose'. A mean population dose in all age groups is just an average dose and not necessarily the best or the correct dose for a given patient. The dose of a drug varies from patient to patient and individual adjustment of the dose is always ideal but is not always practical. Theoretically, dose selection in paediatric drug development or clinical settings can be done by using either body weight or the clearance of a drug. Over the years, a lot of approaches have been suggested for the prediction of drug clearance or dose in paediatrics. Although some proposed methods are useful for the prediction of clearance or dose in children, there remains a high degree of uncertainty in the prediction of drug clearance or dose in children. In particular, the prediction of clearance or dose in an individual patient remains highly erratic. This review takes a critical look at these approaches and highlights the application and limitations of these proposed methods.

Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% confidence interval, 50%-75%), and all CRs had MRD <0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurologic events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit-risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval. See related commentary by Geyer, p. 1133 Nonclinical Pharmacology and Toxicology Nonclinical safety studies were conducted with lentivirustransduced T cells prepared from healthy donors and patients in