Vonjo
pacritinib
Sources:FDA integrated review ↗
Species
MouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”
Why that species
Metabolic profile similar to humans and sufficient bioavailability
“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“there were no cardiovascular effects attributed to the administration of pacritinib in the repeat-dose toxicity study in dogs dosed up to 14.2 mg/kg BID for 39 weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”
Pivotal GLP studies
26-week mouse and 39-week dog oral studies
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”
Route in tox
Oral (capsules in dogs)
“39-Week Oral (Capsules) Toxicology Study in Beagle Dogs (RPT241)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (CHO) and in vivo mouse micronucleus assays
“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”
Carcinogenicity
2-year rat and 26-week Tg(HRAS) mouse: not carcinogenic
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Reproductive & developmental
Mouse EFD: post-implantation loss, lower fetal weight and cleft palate at maternally toxic high dose
“The NOAEL for embryo-fetal development was also considered the MD based on higher post-implantation loss, lower mean fetal body weights, and altered external fetal morphology (cleft palate) observed in the presence of maternal toxicity at the HD.”
Safety pharmacology
hERG IC50 3 µM, substantially above free plasma concentrations at clinical exposure
“Pacritinib inhibited human ether-à-go-go-related gene (hERG) potassium channel with a mean IC50 of 3μM, substantially higher than free plasma concentrations at clinical exposure”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Vonjo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: 39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose (FDA integrated review, p. 118)
NOAEL / key findings
39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose
“The Reviewer agreed with the Applicant’s interpretation that the NOAEL was the MD (20 mg/kg/day) based on the mortality, weight loss and GI toxicity observed at the HD.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid tissue depletion with white blood cell changes consistent with bone marrow suppression in mice, rats and dogs
“Lymphoid tissue depletion and concomitant changes in white blood cell parameters, consistent with bone marrow suppression, were observed in mice, rats, and dogs”
Biodistribution & persistence
Mouse: lung exposure 19-fold and brain exposure 2-fold that of plasma
“Pacritinib exposure levels within these three tissues were highest in the lungs (increased 19-fold versus plasma, area under the concentration-time curve [AUC]) followed by the brain (increased 2-fold versus plasma, AUC) and plasma.”
Modality-specific risk
Toxicities at exposures significantly below clinical exposure (no safety margins)
“The toxicities observed in nonclinical studies occurred at exposures that were significantly lower than those anticipated at the proposed therapeutic dose (Table 27).”