Cancer Treatment Today

280mg is FDA approve; 420mg is often used for mantle-cell lymphoma (MCL) and marginal zone lymphoma. However, the initial 2013 review by the US Food and Drug Administration (FDA) noted that doses >2.5 mg/kg daily appeared excessive: “We recommend you evaluate lower doses of ibrutinib in future clinical development as data from the phase 1 trial PCYC-04753 showed that maximum BTK occupancy and maximum response were achieved at doses of >=2.5 mg/kg.”8 Despite this FDA recommendation, all subsequent trials of ibrutinib were conducted with doses of 420 and 560 mg daily. The company that markets ibrutinib, Pharmacyclics, obtained method-of-treatment patents for its multiple indications, all of which exclude the lower dose recommended by the FDA, which has been described as “negative innovation.”
Ratain et al wrote: ” We do not suggest that hematologists abandon ibrutinib, a drug that has been prescribed to many patients without mishap. However, if BTK inhibition is desirable and CSK inhibition is undesirable, the goal should be to administer a dose that adequately inhibits BTK, while minimizing inhibition of CSK. That is readily achievable, as ibrutinib’s inhibitory concentration (IC50) for BTK is 0.5 nM, whereas its IC50 for CSK is 2.3 nM, a 4.6-fold therapeutic index.7 Lower doses of ibrutinib (eg, 140 mg daily, consistent with the 2013 FDA recommendation) would be expected to maintain BTK inhibition and efficacy, while eliminating or reducing the risks of AF (and possibly also hemorrhage). A small pilot study has demonstrated that ibrutinib’s BTK occupancy and pharmacodynamics are unaffected by reduction to 140 to 280 mg daily.”.

Nevertheless, the fact remains that most literature reports teh use of 560mg per day. Clearly this disrepane needs to be fixed; however, until such a time, the literature supports this dosing.
Ratain MJ, Tannock IF, Lichter AS. The dosing of ibrutinib and related Bruton’s tyrosine kinase inhibitors: eliminating the use of brute force. Blood Adv. 2022 Sep 13;6(17):5041-5044.

Imbruvica Presexcribing Information 2023

NCCN B-cell Lympomas 2023Ratain MJ, Tannock IF, Lichter AS. The dosing of ibrutinib and related Bruton’s tyrosine kinase inhibitors: eliminating the use of brute force. Blood Adv. 2022 Sep 13;6(17):5041-5044.

Imbruvica Presexcribing Information 2023

NCCN B-cell Lympomas 2023