M. Amantea et al., Relationship of dose intensity to the induction of palmar-plantar erythrodysesthia by pegylated liposomal doxorubicin in dogs, HUM EXP TOX, 18(1), 1999, pp. 17-26
The multiple dose pharmacokinetics of pegylated liposomal doxorubicin (PL-D
OX), known as DOXIL(R) (US) and CAELYX(R) (EU), was characterized in dogs a
nd a pharmacokinetic/pharmacodynamic model to identify a relationship betwe
en drug exposure and the probability of observing treatment-related palmar-
plantar erythrodysesthesia (PPE) was developed,
2 Twenty dogs were assigned to PL-DOX groups (2/sex/group) that received in
travenous PL-DOX doses of 0.5 mg/kg q1, 2, or 4 weeks; 1.0 mg/kg q2weeks; o
r 1.5 mg/kg q4weeks for 12 weeks. Blood was collected for HPLC analysis of
doxorubicin concentration predose and periodically up to 120 h after dosing
three times during treatment.
3 Plasma drug concentration was modeled using iterative 2-stage analysis. D
ermal lesions (PPE) were scored twice weekly for six regions of each dog us
ing a 0 - 6 severity scale; maximum severity was 36, PPE score data were mo
deled using an approach in which the % probability of PPE was related to a
hypothetical effect site by a series of Hill-type functions.
4 Pharmacokinetics were best modeled as a one-compartment open model, Vss (
ml/kg), CLt (ml/hr/kg) and half-life (h) were 44.1, 1.39 and 23.1, respecti
vely. Cmax increased linearly with dose. CLt decreased with repeated doses,
5 A two-compartment pharmacodynamic model, which correctly predicted 97% of
the observed lesion severity, was developed to establish the relationship
of lesion severity to dose intensity (a measure of drug exposure incorporat
ing the effect of both dose level and dosing frequency, which can be expres
sed in units of mg/kg/week), The model demonstrated that maximal PPE was po
sitively correlated with dose intensity, the major factor that affects the
incidence and severity of dermal lesions.
6 The model can be used to predict acceptable dose intensities in humans ut
ilizing body surface area conversion factors and comparative AUCs for dogs
and humans. It predicts that a dose intensity of 10-12.5 mg/m(2) of PL-DOX
will be well tolerated in patients. The results of recent clinical studies
are consistent with this prediction.