Xenleta
lefamulin
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Lefamulin was evaluated in 4-week oral toxicology studies in rats and cynomolgus monkeys.”
Why that species
Major human metabolite BC-8041 is present in both rat and monkey
“The major human lefamulin metabolite, BC-8041 (2R-hydroxy-lefamulin), is present in rat and monkey, the species used in the pivotal toxicology studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week repeated dose toxicity study in monkeys, a formulation containing 6.67 mg/mL lefamulin dissolved in 10 mM citrate-buffered saline was tolerated for approximately 6 weeks”
Study lengthopen answer page →
Longest pivotal study
13 (13-week IV studies)
“No systemic target organ was identified in studies up to 13 weeks of administration.”
Pivotal GLP studies
13-week IV (every 12 hours) rat and monkey studies
“In rats, local intolerance was not observed with a formulation containing 1.875 mg/mL lefamulin dissolved in 10 mM citrate-buffered saline when injected every 12 hours for 13 weeks. In a 13-week repeated dose toxicity study in monkeys”
Route in tox
Intravenous and oral
“In repeat dose studies in both rats and monkeys, local intolerance was dose limiting by both oral and IV routes of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in in vivo rat bone marrow micronucleus and in vitro mouse lymphoma assays
“Lefamulin did not elicit genotoxic potential in an in vivo rat bone marrow micronucleus assay for clastogenicity or in the in vitro Mouse Lymphoma Ly5178Y TK+/- mutation assay.”
Carcinogenicity
Not conducted (short-duration clinical use)
“No carcinogenicity studies have been carried out, as the expected clinical use is of short duration.”
Reproductive & developmental
Rat and rabbit EFD; reduced live birth index in rats at high doses
“Effects on embryo-foetal development were evaluated in rats and rabbits. Overall, a reduced live pup birth index in rats indicated an effect of lefamulin on embryo-foetal survival at high doses”
Safety pharmacology
hERG IC50 27 µM (CHO) and 47 µM (HEK-293); action potential prolongation in rabbit Purkinje fibres
“The IC50 for lefamulin at the hERG channel is 27 µM in CHO cells and 47 µM in HEK-293 cells. In rabbit Purkinje fibres, the potential to prolong the duration of the action potential was observed.”
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 Xenleta 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Administration-site reactions dose-limiting in rats and monkeys; no systemic target organ up to 13 weeks (EMA assessment report, p. 39)
NOAEL / key findings
Administration-site reactions dose-limiting in rats and monkeys; no systemic target organ up to 13 weeks
“With IV administration, tolerability was limited by local reactions at the administration site in both rats and monkeys. No systemic target organ was identified in studies up to 13 weeks of administration.”
Risksopen answer page →
Immune & cytokine safety
Splenic lymphoid sheath reduction and thymic cortical atrophy in rats after IV dosing
“Following IV administration of lefamulin to rats for 4 or 13 weeks, anemia (all doses), increased coagulation times, and lower organ weights and histopathological changes in spleen (decreased peri-arteriolar lymphoid sheath, decreased size of the marginal zone) and thymus (cortical atrophy) were seen in rats”
Biodistribution & persistence
Rapid, wide tissue distribution in rat QWBA; skin, soft tissues and lung exceed blood levels
“A quantitative whole-body autoradiography in rats after IV bolus administration showed a rapid distribution into tissues and organs consistent with the apparent low protein binding affinity observed in vitro.”
Modality-specific risk
QT/QTc prolongation (dose-dependent in telemetered monkeys)
“In telemetered monkeys (study SNBL.289.02), dose-dependent QT/QTc interval prolongation was observed.”