Molnupiravir Poisons Bone Marrow when it is Needed Most

7 days at 0.4x human dose (in dogs) is equivalent or exceeds 2.8 days at the human dose. Thus, the human bone marrow is already impaired on the day 3. Production of B-cells and other immunity functions are weakened. This is consistent with the clinical trials’ results: the patients given Molnupiravir within the first 3 days from symptoms onset had much worse outcomes than the patients given Molnupiravir later. This is because the bone marrow has already done its job creating B-cells to fight SARS-COV-2 after 3 days from symptoms onset, typically.

Bone marrow toxicity of Molnupiravir, in the Merck’s own brief:

Bone marrow/hematopoietic findings 

In the 1-month repeat-dose toxicity study in dogs (doses of 6, 17, and 50 mg/kg/day), mild dose-related hematologic findings affecting all cell lines were observed following 7 days of dosing. 

More severe hematologic changes were apparent after 14 to 21 days of continuous dosing leading to pancytopenia, including severe thrombocytopenia and associated hemorrhage at 17 mg/kg/day (0.4-fold the clinical NHC AUC0-24hr exposure) and 50 mg/kg/day (2-fold the clinical NHC AUC0-24hr exposure). This resulted in early termination of treatment at 50 mg/kg/day after 2 weeks and at 17 mg/kg/day after 3 weeks. These hematologic changes were secondary to decreased cellularity of the bone marrow hematopoietic precursors (bone marrow depletion) observed at postmortem examinations. The hematopoietic changes were fully reversible at 17 mg/kg/day with essentially normal bone marrow and hematologic parameters following a 1-month recovery period. Animals in the 50 mg/kg/day group were euthanized approximately 10 days after treatment termination; hematopoietic changes were partially reversible during the shortened recovery period. Only minor, reversible, nonadverse hematopoietic changes were seen in animals administered 6 mg/kg/day for 28 days. The NOAEL in dogs was therefore 6 mg/kg/day (0.1-fold the NHC AUC0-24hr exposure at the 800 mg Q12H human dose). These hematopoietic findings are of low risk for the proposed patient population. Hematologic changes observed after 7 days of dosing in dogs in the 28-day study were relatively mild compared with later time points and the bone marrow and hematologic changes demonstrated reversibility upon discontinuation of treatment. The proposed duration of treatment for COVID-19 is 5 days, and the clinical safety database shows no hematologic effects indicating bone marrow toxicity [Sec. 4.4]
  Target organs identified in the pivotal repeat-dose studies were the bone marrow (in dogs only) and the growth plate (in rats only). Reversible hematopoietic findings affecting all cell lines was observed in dogs only. Hematologic changes were mild after 7 days of MOV administration and were more severe after 14 days of dosing.   

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