UPFRONT LOW DOSE NILOTINIB IN CML CP PATIENTS IN INDIAN SCENARIO – A RANDOMIZED PHASE II ACTIVE CONTROL STUDY

As  the maximum dose of nilotinib is 400mg BD ,after  further increasing dose doesn’t produce any appreciable increase in exposure

Dose of 300 mg BD was found to be sufficient to produce clinical benefit in patients of CML-CP

It has been shown in some studies that 400 mg OD also produces sufficient drug levels that are sufficient to inhibit BCR-ABL activity

Thus 300mg BD could possibly a higher dose and further  lower doses of nilotinib could produce a similar clinical benefit

Food increases the bioavailability of nilotinib

A fatty meal sufficient enough to increase absorption will again increase nilotinib drug levels compare to fasting state

Also its difficult for patient to maintain a fasting state i.e. drug either 2 hours after a meal and 1 hour before meals

As drug is to be taken two times a day, it creates a difficult and stringent schedule for patient. If it allowed with food schedule will be more convenient for patients

Nilotinib being a potent second generation TKI is more potent than Imatinib

The recommended dose as per literature review is 300 mg BD or 400 mg BD in chronic phase CML

This has to be given in empty/fasting state to avoid variability in Pk/Pd.

Nilotinib being much potent , helps to achieve MMR early and make the patient TFR eligible .Its also effective in Imatinib resistant cases which are present in approximately 10 % in primary setting; it also prevents conversion from Chronic to accelerated/blast phase which  has deep impact on OS (~10 months after conversion) . So currently standard of care is nilotinib.

Original Nilotinib that comes as brand name tasigna costs around Rs. 7500 for 10 capsule of 200 mg dose. So tasigna as per this price and dosing schedule i.e. 300 mg bd costs around Rs 1.2 lakh .However generic nilotinib  at this recommended dose, it costs range between Rs.7000 -10000 for different companies. Similarly , at the same time Generic Imatinib at standard approved dose of 400 mg in chronic phase CML costs around ~Rs-600 -2500 for 1 month.  As India comes under Low middle Income countries , so it’s a great financial burden to Indian population which is in majority belongs to middle class families. To avoid this financial toxicity, most Indian centres uses Imatinib 400 mg dose which is available at very reasonable amount. Indian people also deserve current standard of care which is followed worldwide. But Indian patients dont prefer to take nilotinib in view of economic constraints. TKI comes with lots of side effects. Imatinib predominantly causes Gastrointestinal tolerance and Musculoskeletal (myalgia) which hampers Quality of life. Nilotinib has also its side effects that include deranged metabolic profile , pancreatitis  and ECG changes .But overall incidence  of serious adverse events is very less. As per long term data of ENESTnd and other published literature, majority of these side effects were noted with dose 300 mg and 400 mg. Grade 4 events that leading to drug discontinuation was very rare.

By using 150 mg in twice daily dosing , we can also see the metabolic profile over 3 months . These 3 months trend of metabolic profile in turn can tell us about expected metabolic events after chronic drug exposure in long run. Simultaneously, it can be compared with current literature regarding further future guidance. So using nilotinib in 150 mg bd , we will be providing current standard of care in our patients. We expect to get superior results with probably less side effects and less economic burden on the patient .Patient don’t need to be empty stomach for taking drug which is also one of the important factor in patient compliance .

Combining the above two factors, dose of nilotinib which is currently in practice, can be brought down from 150mg BD to further lower levels. This will decrease the cost of therapy too and financial toxicity .