Oral Presentation: The Risk of Oligospermia with Tyrosine Kinase Inhibitors: A Disproportionality Analysis from Vigibase and AERS Databases

• Published in: Drug safety Vol. 45; no. 10; p. 1125
• Main Authors: Velez, L, Das, A, Parulekar, V, Chhabra, N, Izquierdo, M, Nicolaides, M, Zeeuw, P D, Rossiter, A, Eisinger, J, Michel, C
• Format: Journal Article
• Language: English
• Published: Auckland Springer Nature B.V 01.10.2022
• Subjects: Angiogenesis; Antiangiogenics; Atrophy; Bayesian analysis; Cancer; Cisplatin; Colchicine; Drugs; Empirical analysis; Gefitinib; Hypotheses; Hypothesis testing; Imatinib; Inhibitors; Kinases; Life expectancy; Life span; Lower bounds; Pharmacovigilance; Product safety; Radiation therapy; Semen; Spermatogenesis; Sulfasalazine; Tyrosine; Tyrosine kinase inhibitors
• ISSN: 0114-5916; 1179-1942

Introduction: Advances in the treatment of cancer in young patients have led to great improvements in life expectancy. However, treatment with chemo or radiotherapy causes reduction of sperm counts often to azoospermic levels that may persist for several years or be permanent. Oligospermia or azoospermia and long-lasting testicular atrophy are common adverse consequences of cancer treatment (1). Objective: To quantify disproportionate reporting (Disp-Rep) (2-4) for the risk of drug-associated oligospermia/azoospermia for 29 tyr-osine kinase inhibitors (TKIs) in 2 groups: (1) Anti-angiogenic (AA) TKIs; (2) Non-anti-angiogenic (NAA) TKIs. Methods: We used the AERS and VigiBase databases, with data up to June 2021 and Oct 2021 respectively for analysis. Cases of oligospermia and azoospermia were identified using MedDRA (v24.0) and the high-level-term (HLT) 'Spermatogenesis and semen disorders' (SSD). Empirical Bayes Geometric Means (EBGM) with 90%CI were calculated to quantify Disp-Rep. We considered Dis-Rep as confirmed if the lower bound, EB05, was > 2. We studied 3 groups of drugs: (1) Positive control group (non-TKIs associated with oligospermia/azoospermia: sulfasalazine, colchicine and cisplatin) and two groups of TKIs: (2) AA TKIs (14 drugs) & (3) NAA TKIs (15 drugs). Drugs were identified by non-proprietary name. Results: We retrieved 101 SSD cases in AERS and 83 in VigiBase. In AERS, Disp-Rep with EBGM [90% CI, EB05-EB95] was confirmed for the positive control group: cisplatin 4.36 [3.31-5.70], and colchicine 3.53 [2.20-5.59] and in VigiBase for sulfasalazine 3.18 [2.07-4.72]. In AERS, Disp-Rep was confirmed for only 1 of 15 NAA TKIs: ibrutinib 3.37 [2.24-4.96]. No Dis-Rep (EB05 < 2) was found for the rest of NAA TKIs: afatinib, bosutinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib and vemurafenib. No Dis-Rep was found for any of the 14 AA TKIs: acalabrutinib, axitinib, cabozantinib, dacomitinib, lenvatinib, neratinib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib and vandetanib. The analysis in VigiBase database yielded similar results. Conclusion: Ibrutinib (NAA TKI) was the only drug among the 29 different TKIs studied with Disp-Rep for oligospermia/azoospermia in both databases. Our results however, should be interpreted with caution as disproportionality analyses are hypothesis generating rather than hypothesis testing.