Pharmacodynamics is often summarized as the study of what a drug does to

the body, whereas pharmacokinetics is the study of what the body does to a
drug.
Pharmacodynamics is the study of the biochemical and physiological effects of
drugs on the body or on microorganisms or parasites within or on the body
and the mechanisms of drug action and the relationship between drug
concentration and effect.[
Pharmacokinetics describes how the body affects a specific drug after
administration through the mechanisms of absorption and distribution, as well
as the chemical changes of the substance in the body, and the effects and
routes of excretion of the metabolites of the drug.
A drug’s bioavailability can be defined as the proportion of the drug that
reaches its site of action. Bioavailability is therefore a mathematical factor for
each individual drug that influences the administered dose.

Pharmacokinetic effects of CPT studied for phase 1 trials

Camptothecin, has inhibitory effects on mammalian DNA topoisomerase I, high
cytotoxic activity in vitro and anticancer activity in animal models.
Administered at dose levels ranging from 50 to 145 mg/m2 (30–90 min i.v.
infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and
appeared to be dose related, reversible and noncumulative. However,
interpatient variability of toxic effects was substantial. Prolongation of the
infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other
toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and
anemia. CPT plasma disposition was bi- or triphasic with a terminal half-life of
9.3 h. CPT area under the plasma concentration versus time curves increased
linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the
plasma concentration versus time curve correlated significantly with that of
CPT, but not with that of CPT dose.
PHASE 2:
Recommended doses for phase II studies are 100 mg/m2 in high risk patients
and 115 mg/m2 in others.

Phase 1 Study of Weekly Polyethylene Glycol-

Camptothecin

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 The maximal tolerated dose was 3,240 mg/m2. Other grade 3 and 4 toxicities
were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin
time, hemorrhagic cystitis, dysuria, and urinary frequency.
Pharmacokinetic analysis showed the apparent terminal elimination half-life to
be 46 ± 12.8 hours.
Pharmacodynamic analysis showed that hematuria occurred in 8 of 15
patients with an area under the curve extrapolated to infinity (AUC0-∞) > 20
ng h/mL and 0 of 10 patients with an AUC0-∞ ≤ 20 ng h/mL. Unconfirmed
partial responses were observed in two patients, one with metastatic small
bowel adenocarcinoma and the other with metastatic esophageal cancer.
Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was
low, but genitourinary toxicity seems to occur in the same effective dose range
as noted with native camptothecin
Pharmacokinetic analysis. Free camptothecin plasma concentrations-versus-
time data were analyzed using noncompartmental methods (15). The apparent
terminal elimination half-life (t1/2) was estimated by linear regression of the
terminal concentration-time data plotted on a log-linear scale. Actual sampling
times and the linear trapezoidal method were used to calculate the area under
the curve extrapolated to infinity.
BIOAVAILABILITY:
Plasma concentrations of the lactone and carboxylate forms of 9-AC rapidly
reached an equilibrium, with the active lactone accounting for < 10% of total
drug at the terminal disposition phase. The drug demonstrated peak levels at
1.2 h and an overall bioavailability of 48.6+/-17.6% (range, 24.5-80.4%),
indicating significant systemic exposure to the drug, which may enable chronic
oral treatment.

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