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”
Species: general tox
Rat and monkey (IV and oral)
“In repeat dose studies in both rats and monkeys, local intolerance was dose limiting by both oral and IV routes of administration.”
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Fertility, embryo-foetal development, pre- and post-natal development and juvenile toxicity studies were conducted in rats, and embryo-foetal development has been assessed in rabbits.”
Species: carcinogenicity
Not conducted (short-duration clinical use)
“No carcinogenicity studies have been carried out, as the expected clinical use is of short duration.”
Surrogate used in
No surrogate used
“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.”
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.”
Genotox: Ames
Negative (concentrations limited by cytotoxicity)
“Lefamulin did not exhibit genotoxic potential in a battery of standard genotoxicity assays. Cytotoxicity limited the concentrations that were used to evaluate the mutagenic potential of lefamulin in the Ames reverse mutation study.”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y TK+/- assay: negative
“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.”
Genotox: in vivo
Rat micronucleus (up to 100 mg/kg/day): negative
“In an in-vivo micronucleus test in rats (≤100 mg/kg/day), there was no evidence of chromosomal damage with lefamulin (AUC0-8 ≤ 26.9 µg.h/mL).”
Carcinogenicity model
Not conducted
“Long-term carcinogenicity studies have not been conducted with lefamulin.”
Carcinogenicity timing
Not conducted; not required for short-duration clinical use
“Carcinogenicity studies were not carried out by the applicant. In line with guidance, carcinogenicity studies are not required if expected clinical use is for a short duration.”
hERG / QT
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- QT Prolongation
- Embryo-Fetal Toxicity
- Clostridioides difficile-associated Diarrhea
- Development of Drug-Resistant Bacteria
CardiovascularEmbryo-fetal toxicityGastrointestinal
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV (every 12 hours) rat and cynomolgus 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, a formulation containing 6.67 mg/mL lefamulin dissolved in 10 mM citrate-buffered saline was tolerated for approximately 6 weeks”
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”
DART package
Species: DART
Rat (fertility, EFD, PPND, juvenile) and rabbit (EFD)
“Fertility, embryo-foetal development, pre- and post-natal development and juvenile toxicity studies were conducted in rats, and embryo-foetal development has been assessed in rabbits.”
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”
PPND / ePPND: when
PPND in rat completed and assessed in the marketing application
“In a prenatal and postnatal study in rats, (AB21312), the pup live birth index was markedly lower at the highest dose tested only (100 mg/kg/day), (with 33 stillborn/dead pups on PND 0 compared with 4 in the control), associated with partial or total litter death of 4/25 litters.”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-duration clinical use)
“No carcinogenicity studies have been carried out, as the expected clinical use is of short duration.”
Carcinogenicity model
Not conducted
“Long-term carcinogenicity studies have not been conducted with lefamulin.”
Carcinogenicity timing
Not conducted; not required for short-duration clinical use
“Carcinogenicity studies were not carried out by the applicant. In line with guidance, carcinogenicity studies are not required if expected clinical use is for a short duration.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey IV NOAEL (120 mg/kg/day) 2.8x (IV) and 2.4x (oral) human AUC
“The steady-state exposure level at the NOAEL of 120 mg/kg/day was 79.7 µg·h/mL for AUC0-24 and 15.8 µg/mL for Cmax, 2.8 and 2.4 times the mean AUC of the clinical IV or oral dose, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Animal infection models of S. pneumoniae and S. aureus pneumonia (PK-PD index fAUC/MIC)
“The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio has been shown to be the best Pharmacokinetic-Pharmacodynamic (PK-PD) index for the antibacterial activity of lefamulin in animal infection models of Streptococcus pneumoniae and Staphylococcus aureus pneumonia.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
Dose considered poorly supported by PK-PD analyses
“Given that the dose of lefamulin is anyway poorly supported by PK-PD analyses, both SmPCs contraindicate use with strong and moderate inducers of CYP3A.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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