Reproductive and developmental toxicity assessment of palbociclib, a CDK4/6 inhibitor, in Sprague-Dawley rats and New Zealand White rabbits

Catlin, Natasha; Bowman, Christopher J.; Engel, Scott; Sacaan, Aida; Thibault, Stéphane; Lewis, Elise M.; Cappon, Gregg D.

doi:10.1016/j.reprotox.2019.07.016

Cited by 14 publications

(4 citation statements)

References 21 publications

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“…The study design, toxicokinetic analysis, and statistical analysis used for the fertility and rat and rabbit EFD studies have been previously described [ 17 , 18 ]. Briefly, in the fertility study estrous cycling was monitored in the female rats 14 days prior to dose initiation, during dosing, and continuing until positive evidence of mating was observed (sperm present in smear of vaginal contents or presence of copulatory plug).…”

Section: Methodsmentioning

confidence: 99%

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Catlin

Bowman

Campion

et al. 2022

Reproductive Toxicology

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Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (M pro ), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.

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Section: Methodsmentioning

confidence: 99%

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Catlin

Bowman

Campion

et al. 2022

Reproductive Toxicology

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“…Interestingly, the gonadotrophs were unaffected, and transplanted blastocysts derived from Cdk4-null oocytes to the uteri of WT mice developed normally, suggesting that the oocytes themselves were unaffected ( Moons et al 2002 ). However, despite these findings in female Cdk4-deficient mice, preclinical studies carried out in rats who were administered doses up to 300 mg/kg/day of palbociclib once daily for 15 days showed no evidence of any impact on fertility, as determined by no deviations in oestrous cyclicity, functional fertility, and uterine parameters ( Catlin et al 2019 ). The authors propose that this finding may reflect the difference between complete absence of Cdk4 during fetal development in knockout mice compared to the transient pharmacological inhibition achieved in their study, thus bringing into question the potential long-term consequences of prolonged CDK4 inhibitor exposure that may be used in a clinical setting, particularly in the curative treatment setting where 2 years of CDK4/6 inhibitor therapy is recommended.…”

Section: Cdk Inhibitorsmentioning

confidence: 94%

Potential ovarian toxicity and infertility risk following targeted anti-cancer therapies

Rosario

Cui

Anderson

2022

Reproduction and Fertility

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Unlike traditional chemotherapy agents which are generally cytotoxic to all cells, targeted anti-cancer therapies are designed to specifically target proliferation mechanisms in cancer cells but spare normal cells, resulting in high potency and reduced toxicity. There has therefore been a rapid increase in their development and use in clinical settings, including in curative-intent treatment regimens. However, the targets of some of these drugs including kinases, epigenetic regulatory proteins, DNA damage repair enzymes and proteasomes, have fundamental roles in governing normal ovarian physiology. Inhibiting their action could have significant consequences for ovarian function, with potentially long-lasting adverse effects which persist after cessation of treatment, but there is limited evidence of their effects on reproductive function. In this review, we will use literature that examines these pathways to infer the potential toxicity of targeted anti-cancer drugs on the ovary.

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“…Upregulation of the signal transducer and activator of transcription 3 (STAT3) pathway in mice has been found to counteract the inhibition of EGFR caused by lapatinib, for example [(Liao et al, 2020)]. This may explain the overall neutral effect on corpora lutea seen in animal models exposed to KI therapy [ (Catlin et al, 2019), (Zhang & Tian, 2020)].…”

Section: Ovarian Functionmentioning

confidence: 99%

Targeted cancer treatment and fertility: effect of immunotherapy and small molecule inhibitors on female reproduction

Bussies

Richards

Rotz

et al. 2022

Reproductive BioMedicine Online

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Targeted cancer therapy is rapidly evolving the landscape of personalized health care. Novel approaches to selectively impeding tumor growth carry significant potential to improve survival outcomes, particularly for reproductive-aged patients harboring treatment refractory disease. Current agents fall within two classes, immunotherapy and small molecule inhibitors, which are collectively divided into the following subclasses: monoclonal antibodies, immunomodulators, adoptive cell therapy, treatment vaccines, kinase inhibitors, proteosome inhibitors, metalloproteinase and heat shock protein inhibitors, and promoters of apoptosis. The short-and long-term effects of these therapies on the female reproductive system are not well understood. As a result, clinicians are rendered unable to appropriately counsel women on downstream effects to their fertility. Data-driven consensus recommendations are desperately needed. This review aims to characterize the impact of targeted cancer therapy on the female hypothalamic-pituitary-ovary axis, direct ovarian function, and conception.

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Reproductive and developmental toxicity assessment of palbociclib, a CDK4/6 inhibitor, in Sprague-Dawley rats and New Zealand White rabbits

Cited by 14 publications

References 21 publications

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Potential ovarian toxicity and infertility risk following targeted anti-cancer therapies

Targeted cancer treatment and fertility: effect of immunotherapy and small molecule inhibitors on female reproduction

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