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Review |
Department of Clinical Pharmacokinetics and Drug Metabolism, Sanofi-Synthelabo Research, Malvern, Pennsylvania 19355 [M. A. G., G. F. L., D. G.]; Debiopharm SA, 1003 Lausanne, Switzerland [S. B., M. B.]; and Center Paul Papin, 49033 Angers, France [E. G.]
ABSTRACT
Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252–273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve0–48) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 ± 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 ± 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients. These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients.
Introduction
Oxaliplatin
(cis-[(1R,2R)-1,2-cyclohexanediamine-N,N']
oxalato (2-)-O,O'] platinum; Eloxatine; Fig. 1
) is a novel platinum coordination
complex recently approved in Europe, Asia, and Latin America for the
treatment of metastatic colorectal carcinoma in combination with
fluoropyrimidines. Oxaliplatin is more potent than cisplatin in
vitro, requiring fewer DNA adducts to achieve equivalent
cytotoxicity (1, 2, 3, 4)
. Oxaliplatin has demonstrated efficacy
in preclinical studies against a broad spectrum of experimental tumors,
including some cisplatin- and carboplatin-resistant cell lines
(2
, 5, 6, 7, 8, 9, 10, 11)
. Clinically, the safety and efficacy of a
variety of dosing regimens with 5-FU and leucovorin have been
evaluated, and the combination has demonstrated marked antitumor
efficacy in patients with a favorable toxicity profile
(12, 13, 14, 15, 16, 17, 18)
. As part of the clinical development program, the
PKs2
of oxaliplatin have been
evaluated by several investigators in several different laboratories.
The main objectives of this review, therefore, are to: (a)
provide a critical assessment of the various PK studies conducted to
date; (b) integrate the key data from these investigations
into a single, comprehensive overview of oxaliplatin disposition in
patients; and (c) identify the PK characteristics of the
drug relevant to the safe and effective use of oxaliplatin in the
clinic.
|
An overview of the design of the various PK and metabolism studies
cited in this review is summarized in Tables 1
and 2
.
The most comprehensive PK studies were conducted in multiple matrices
(plasma, ultrafiltrate, and blood) and originate from three main
studies (19, 20, 21, 22, 23)
. In the PK studies reported by
Graham et al. (19
, 20) , the multiple dose PKs
of platinum were analyzed in six patients treated with 130
mg/m2 oxaliplatin every 3 weeks for five cycles.
This study provided detailed kinetic data in a variety of matrices with
PK monitoring over a 3-week period and enabled platinum accumulation to
be assessed after multiple dosing. In other studies reported by
Allen et al. (21
, 22)
, the single dose PKs,
biotransformation, and excretion of platinum were explored in a total
of 20 patients receiving 130 mg/m2 oxaliplatin.
In these studies, the first five patients were enrolled for the
assessment of oxaliplatin biotransformation and excretion (with limited
PK sampling). The remaining 15 patients then underwent a full PK
analysis. As an extension to this study, the multiple dose PKs of
oxaliplatin were investigated in six additional patients after a 2-h
infusion at 85 mg/m2 every 2 weeks for three
cycles (24)
. All of the above studies were supported by
fully validated ICPMS bioanalytical method for platinum in
ultrafiltrate, plasma, and blood (25
, 26)
. The PKs of
platinum (expressed as oxaliplatin equivalents) after a 4-h infusion
schedule has also been reported by Kern et al.
(23)
in plasma and ultrafiltrate. Supportive PK studies,
generally limited to measuring total plasma platinum levels, have also
been conducted by a number of other investigators using a variety of
FAAS and ICPMS methods (27, 28, 29, 30)
.
|
|
A comprehensive characterization of the major routes of oxaliplatin biotransformation and elimination in patients receiving a single i.v. infusion of oxaliplatin at 130 mg/m2 has been reported by Allen et al. (21 , 22) . These studies investigated the major oxaliplatin biotransformation products in plasma ultrafiltrate and urine samples from patients by liquid chromatography-mass spectrometry. These studies also examined platinum excretion in the urine and feces of cancer patients receiving oxaliplatin. Other supportive platinum mass balance results in urine and feces using nonvalidated bioanalytical methods have been reported by several investigators, with good agreement in the derived estimates across all studies (19 , 20 , 23 , 28 , 30) .
The PKs of platinum in special patient populations have been examined in two studies by Massari et al. (35) and Graham et al. (36) . Massari et al. (35) investigated the effect of moderate renal impairment on the clearance of platinum and toxicity of oxaliplatin in cancer patients after a single dose at 130 mg/m2. In the study by Graham et al. (36) , a meta-analysis of oxaliplatin PKs was conducted to investigate the effect of age, sex, and renal and hepatic function on the clearance of ultrafilterable platinum in cancer patients.
Finally, potential PK interactions after a single 2-h infusion of oxaliplatin at 130 mg/m2 and 5-FU (de Gramont regimen) have been examined by Papamichael et al. (37 , 38) in a one-way interaction study. Details of other in vivo and in vitro drug-drug interaction studies are also reviewed in this article.
Selection of Analyte and Matrix for PK Studies
Oxaliplatin rapidly forms a variety of reactive intermediates in blood and plasma, including the monochloro-, dichloro-, and diaquo-platinum species. These reactive platinum complexes can bind irreversibly to various constituents in the blood and/or cellular macromolecules. Ultimately, the products of these reactions are eliminated as nonreactive small molecular weight conjugates. Given the rapidity of these reactions both in vitro and in vivo, investigating the PKs of intact parent compound or one of the transient intermediates is technically difficult and not feasible for routine PK assessment. Hence monitoring platinum PKs rather than intact parent compound (or a metabolite) is a generally accepted approach that has been adopted for the analysis of other platinum complexes published in the literature (for a review, see Ref. 39 ).
For a full description of platinum PKs, it is useful to discriminate between bound and free platinum in blood and plasma. Ultrafilterable platinum (comprising nonprotein bound drug and biotransformation products in plasma water) is thought to represent all the platinum species with antitumor and toxic properties in the circulation. Unbound platinum is cleared from the systemic circulation by a combination of irreversible binding to plasma/blood constituents, tissue uptake, and urinary elimination. Platinum irreversibly bound to plasma proteins and erythrocytes is generally considered to be pharmacologically inactive (39) . Therefore, plasma ultrafiltrate represents the most relevant matrix when considering pharmacological activity.
The most comprehensive PK studies presented in this review were conducted in plasma ultrafiltrate, as well as plasma, blood, and blood cells (19, 20, 21, 22, 23, 24) . In a number of earlier studies, platinum measurements were only obtained in plasma and blood samples (27, 28, 29, 30 , 40) . Therefore, plasma platinum measurements were used to make PK comparisons across all studies.
PKs of Oxaliplatin
A summary of the main PK parameters in plasma across all studies
conducted to date is presented in Table 3
. The studies provided consistent
parameter estimates for plasma platinum Cmax and
AUC (Table 3)
. After a dose of 130 mg/m2 infused
over 2 h, mean Cmax values were in the range
of 2.59–3.22 µg/ml and mean AUC0–48 values
were in the range of 50.4–71.5 µg/ml·h (Table 3)
.
|
Assessment of dose proportionality for total plasma platinum was
conducted as part of the Phase I study reported by Taguchi
(27)
. Oxaliplatin was administered as single 1-h infusion
in a total of 17 patients over the dose range 20–180
mg/m2. The mean Cmax and
AUC0–24 increased in a dose related manner up to
180 mg/m2. The relationship between plasma
platinum AUC and dose is presented in Fig. 2
.
|
The effect of infusion duration on plasma platinum Cmax was investigated as part of study by Marty et al. (28) . Prolongation of the infusion from 2 to 6 h has been used to circumvent the acute laryngopharyngeal dysestheias observed in certain patients.
Analysis of plasma platinum Cmax values after a
1-h infusion (dose normalized to 130 mg/m2)
indicated that prolonging the infusion from 1 to 6 and 12 h
decreased the mean Cmax by approximately 56 and
71%, respectively (Fig. 3)
. Although 2-h
infusion data were not included in this study, the levels at 1 and
6 h encompass the typical mean plasma Cmax
values after a 2-h infusion (2.96 ± 0.57 µg/ml; Table 3
). The
percentage of decrease in Cmax produced by
increasing the duration of infusion from 2 to 6 h was estimated to
be approximately 32%.
|
Multiple dose PK analysis of platinum in plasma ultrafiltrate, plasma, and blood cells has been investigated after oxaliplatin infusions at 85 and 130 mg/m2 (19 , 20 , 24) .
Platinum PKs have been monitored in six patients receiving five
consecutive cycles of treatment at 130 mg/m2
every 3 weeks (19
, 20)
. The multiple dose PK data at 130
mg/m2 in ultrafiltrate, plasma, and blood cells
are presented in Fig. 4
. No accumulation
was observed in plasma ultrafiltrate after 3–5 cycles of treatment.
Limited platinum accumulation (
2-fold) was observed in plasma and
blood cells (Fig. 5)
.
|
|
. No accumulation
was observed in ultrafiltrate and plasma after three cycles of
treatment and platinum only accumulated to a limited extent in blood
cells (<2 fold) after multiple doses at 85 mg/m2
(Fig. 5)
. Similar clearance values after a dose of 85
mg/m2 have also been reported by Lokiec et
al. (41)
after PK studies with oxaliplatin in
combination with CPT-11.
|
After a 2-h infusion of oxaliplatin at 130 mg/m2 every 3 weeks, mean (±SD) Cmax values in plasma ultrafiltrate on cycle 5 were approximately 1.21 ± 0.10 µg/ml. Mean Cmax values in plasma and blood cells were approximately 3.61 ± 0.43 and 3.25 ± 0.49, µg/ml respectively (cycle 5; Refs. 19 and 20 ). Mean Cmax values in plasma ultrafiltrate, plasma, and blood cells after a 2-h infusion of oxaliplatin at 85 mg/m2 every 2 weeks for three cycles were 0.681 ± 0.077, 1.92 ± 0.338, and 2.67 ± 0.798 µg/ml, respectively, on cycle 3 (24) .
Platinum Exposure (AUC)
After a 2-h infusion of oxaliplatin at 130 mg/m2, AUC0-inf values in plasma ultrafiltrate (cycle 1) were 11.9 ± 4.60 µg·h/ml. AUC0-inf values in plasma and blood cells (cycle 1) were typically 207 ± 60.9 and 1326 ± 570 µg·h/ml, respectively (19 , 20 , 22) .
Mean (±SD) AUC0-inf values (cycle 1) in plasma ultrafiltrate, plasma, and blood cells after a 2-h infusion of oxaliplatin at 85 mg/m2 were 4.25 ± 1.18, 118 ± 8.97, and 252 ± 34.6 µg/ml·h, respectively (24) .
Platinum Half-life (t1/2)
In the studies monitoring PK of platinum over 2–3 weeks
posttreatment, the PKs of platinum in ultrafiltrate were
triexponential, characterized by short initial 
and ß distribution
phases (0.28 and 16.3 h, respectively) followed by a long terminal
-phase (273 h; Refs. 19
and 20
).
The short initial half-life of platinum in plasma ultrafiltrate probably represents the rapid clearance of intact oxaliplatin and the reactive dichloro-, monochloro-, and diaquo-DACH platin intermediates into tissues and/or removal from the systematic circulation via glomerular filtration. The long terminal half-life of unbound platinum in plasma ultrafiltrate probably represents the slow release of low molecular weight platinum-amino acid conjugates after the degradation of cellular macromolecules, such as proteins (19 , 20) .
The apparent differences in the terminal half-life estimates between
studies for total plasma platinum and ultrafiltrate (Tables 3
and 4)
is
likely to be due to two main contributory factors: first, differences
in the frequency and duration of sample collection (Table 1)
; and
second, differences in detection limits between FAAS and ICPMS
(approximately 50 and 1 ng/ml, respectively). For example, the terminal
half-life of platinum estimated by Kern et al.
(23)
was approximately 27.3 ± 10.6 h in plasma
ultrafiltrate. However, blood sampling was only conducted over a 24-h
period, which results in an imprecise estimate of the terminal
elimination phase. In contrast, in studies in which complete PK
monitoring was conducted 2–3 weeks posttreatment and using a more
sensitive ICPMS method, the terminal half-life of platinum in
ultrafiltrate was estimated to be 273 ± 19.0 h (19
, 20)
.
The latter half-life estimate of 273 h represents a more rigorous
and precise evaluation of the terminal half-life of platinum after
oxaliplatin administration. However, the half-lives of the shorter
and ß phases (0.28 and 16.3 h, respectively) probably represent
the more clinically relevant t1/2
values of pharmacologically active platinum, given that the platinum in
the terminal elimination phase will comprise almost entirely of
inactive platinum conjugates (21
, 42)
.
Platinum Clearance
The clearance of ultrafilterable platinum was relatively high,
with estimates ranging from 9.34 ± 2.85 to 10.1 ± 3.07
liters/h at 130 mg/m2 (20
, 22)
to
18.5 ± 4.71 liters/h at 85 mg/m2
(24
; Table 4
). Platinum clearance was similar to or
exceeded the average human glomerular filtration of approximately 7.5
liters/h. The renal clearance of ultrafilterable platinum has been
shown to be significantly correlated with GFR, indicating that
glomerular filtration is a principal mechanism of platinum clearance
after oxaliplatin administration (36)
.
Clearance of platinum from plasma and blood cells was relatively low, which is probably a reflection of the covalent binding of platinum to these matrices (19 , 20) .
Platinum Volume of Distribution (Vss)
Platinum has a high volume of distribution from plasma
ultrafiltrate ranging from 349 ± 132 to 812 ± 369 liters
(Refs. 19
and 20
; Table 4
). This high volume
of distribution may be due to the lipophillic nature DACH platinum
complexes and the subsequent irreversible binding of platinum to
proteins, DNA, and other cellular macromolecules.
Platinum Accumulation (Rac)
No significant accumulation has been observed in plasma
ultrafiltrate after multiple dosing at 130 mg/m2
every 3 weeks (19
, 20
, 29) or 85
mg/m2 every 2 weeks (24)
. The
AUC0–48 accumulation ratios in ultrafiltrate,
plasma and blood cells at 130 mg/m2 every 3 weeks
are shown in Fig. 5
. Although platinum has a long terminal half-life in
ultrafiltrate (273 h), the lack of accumulation in this matrix is
probably due to the fact that the terminal portion of the curve
contributes little to the overall AUC and there is negligible carryover
into the next cycle.
Negligible accumulation of platinum was observed in plasma at 130 mg/m2 [cycle 5/cycle 1 AUC0–48 accumulation ratio = 1.33 (95% CI = 1.24–1.42); Refs. 19 , 20, and 29 ]. Similar results were also obtained after multiple dosing at 85 mg/m2 every 2 weeks [cycle 3/cycle 1 AUC0–48 accumulation ratio = 1.04 (95% CI = 0.72–1.51); Ref. 24 ].
Statistically significant accumulation in blood cells [cycle 5/cycle 1 AUC0–48 accumulation ratio = 2.05 (95% CI = 1.81–2.32)] was observed after oxaliplatin administration at 130 mg/m2 every 3 weeks (19 , 20 , 29) . Some accumulation was also observed in blood cells with the 85 mg/m2 every 2-week dosing regimen [cycle 3/cycle 1 AUC0–48 accumulation ratio = 1.94 (95% CI = 1.39–2.71); Ref. 24 ].
Blood cell accumulation has been reported for other platinum complexes, but to a lesser degree (43) .However, the pharmacological significance of blood cell accumulation is limited given the irreversible binding of platinum to this matrix and the lack of platinum efflux in in vitro experiments (7 , 19 , 20 , 29) .
Platinum Accumulation and Steady State (Css)
Attainment of steady state was determined by measuring trough concentrations in plasma ultrafiltrate after five consecutive 3-week cycles of oxaliplatin at 130 mg/m2. No accumulation of platinum was observed in ultrafiltrate, and steady state was achieved on cycle 1 (19 , 20) .
No formal analysis of steady state levels after multiple dosing at 85 mg/m2 has been made, as only three cycles of treatment were evaluated (24) . However, no accumulation was observed in plasma ultrafiltrate, an observation consistent with steady state being reached on cycle 1.
Variability in Ultrafilterable Platinum PKs
Moderate to low between-patient and within-patient variability was observed in ultrafilterable platinum levels over five cycles of treatment. The between- and within-patient variability in ultrafiltrate concentration at the end of infusion (Cend) was 18 and 13%, respectively, and 33 and 5% for the between- and within-patient variability in AUC0–48. (19 , 20) .
Platinum Distribution In Vitro and In Vivo
Binding of Platinum to Plasma Proteins.
The extent of platinum binding to human plasma proteins has been
investigated in vitro over the concentration range 0.3–20
µg/ml oxaliplatin after incubation at 37°C for 6 h (serum) or
24 h (purified protein solutions; Ref. 44
). The
binding kinetics were determined by ultrafiltration and platinum levels
were assayed by FAAS.
The binding of platinum to serum was moderate (79–87%) and time dependent. Equilibrium was attained after 6 h for serum and after 24 h for albumin. Most of platinum was found to be covalently bound. There was no evidence of saturable binding over the concentration range 0.3–20 µg/ml (44) .
The main serum binding proteins were found to be albumin and gamma-globulins (44) . Similar in vitro binding studies were performed by Pendyala and Creaven (7) , except that plasma, rather than serum protein, was used. The binding of oxaliplatin derived platinum to plasma protein was found to be moderate, with 85–88% of the total platinum bound within 5 h.
The plasma protein binding of platinum has also been investigated in patients receiving 130 mg/m2 oxaliplatin by 2-h infusion every 3 weeks for five cycles (n = 6 patients; Refs. 19 and 20 ). At the end of infusion at 2 h on cycle 5, the mean percentage of platinum bound to plasma protein was 65.5 ± 4.89%, which progressively increased to 90.3 ± 1.75% at 6 h and to 98.0 ± 0.42% by 3 weeks.
Similar in vivo protein binding results have also been reported by Misset and Allain (30) . On day 1 at 2 h posttreatment, plasma protein binding was estimated at 70%. Five days posttreatment, with oxaliplatin at 130 mg/m2, plasma protein binding was estimated to be >95%.
Binding of Platinum to Erythrocytes.
Platinum has been shown to irreversibly bind to and accumulate in
erythrocytes (7)
. The half-life of erythrocytic bound
platinum is therefore likely to be determined by the rate of
erythrocyte turnover (19
, 20)
. Blood cell associated
platinum is not considered to be a reservoir of pharmacologically
active platinum due to the irreversible nature of the binding and the
lack of platinum efflux in in vitro experiments (7
, 19
, 20)
.
Although platinum binds to blood cells, the blood cells only represent a minor compartment for drug distribution in patients (19 , 20) . At the end of infusion (2 h), approximately 15% of the administered platinum is present in the blood. The remaining 85% has undergone distribution from the plasma into tissues or has been subjected to urinary elimination. Therefore, platinum distribution to blood cells represents a relatively small component when consideration is given to the total body disposition of platinum.
Binding of Platinum to Lymphocytes.
The uptake of platinum into peripheral lymphocytes of patients has been
investigated after multiple doses of oxaliplatin at 130
mg/m2 (45)
. Platinum was found in
DNA extracts from all oxaliplatin treated patients 1 h after the
end of infusion on cycles 1 and 3. The removal of platinum adducts was
rapid. In four of six patients, no platinum was detected 24 h
posttreatment on cycle 1, and platinum levels could only be detected in
one of six patients on day 5.
Biotransformation and Metabolic Fate of Oxaliplatin
Metabolism and Biotransformation Overview.
Oxaliplatin undergoes a series of spontaneous, nonenzymatic conversions
in biological fluids, a process referred to as drug biotransformation.
These reactions are mediated primarily through the displacement of the
oxalate group by H2O and endogenous nucleophiles,
such as Cl- and
HCO3- ions. Several transient
reactive species are formed, including dichloro-, monochloro-, and
diaquo-DACH platin, which can complex with amino acids, proteins, DNA,
and other macromolecules in plasma and tissues (Fig. 6
; Refs. 21
and
22
).
|
Drug Metabolism Studies.
The biotransformation of [3H]oxaliplatin was
investigated using human liver microsomal fractions in vitro
(31)
. Human liver microsomes were prepared from three
human livers with high CYP450 activity.
After a 30-min incubation of [3H]oxaliplatin with human hepatic microsomes in the presence of NADPH, most of the radioactivity (67%) was associated with unchanged drug. Another major component, which comprised 17% of the total radioactivity, co-eluted with the diaquo-DACH platin standard. Several other minor products were also detected, each representing less than 1–3% of the radioactivity. Similar results were obtained in the absence of NADPH (71% co-eluting as unchanged drug and 17% as diaquo-DACH platin) and using heat-denatured microsomes, indicating that the biotransformation of oxaliplatin was nonenzymatic and occurred by chemical degradation.
In summary, no oxidative metabolism of the DACH group was detected in vitro. [3H]Oxaliplatin was stable to oxidative CYP450-mediated metabolism and degraded nonenzymatically to a single major product, tentatively identified as diaquo-DACH platin (31 , 32) .
Biotransformation Studies in Vitro.
The in vitro biotransformation and distribution of
[3H]oxaliplatin has been investigated in plasma
ultrafiltrate, urine, and whole blood samples (33
, 34)
.
[3H]Oxaliplatin underwent extensive biotransformation in plasma ultrafiltrate and urine. At least 17 radioactive products were observed by HPLC in plasma ultrafiltrate at 24 h, the major ones of which chromatographed with DACH platinum adducts of methionine (6%), monochloro (37%), monochlorocreatinine (9%), dichloro (10%), and monocreatinine (4%). A major unidentified product (SP21; 10%) was also evident. A similar profile was observed at 24 h, and five additional products were also detected, one of which was tentatively identified by mass spectrometry as monochloro urea DACH platin (11%; Refs. 33 and 34 ).
At least 16 radioactive products were present in vitro in urine after incubation with oxaliplatin, the major ones of which were characterized by mass spectrometry and included dicreatinine (24%), methionine (6%), monochloro (2%), monochlorocreatinine (14%), dichloro (7%), and monocreatinine (11%) DACH platins. Diaquo-DACH platin (6%) was tentatively identified by HPLC (34) .
In summary, the in vitro biotransformation studies in plasma ultrafiltrate, urine, and whole blood corresponded closely to the profile of oxaliplatin biotransformation products characterized in the ultrafiltrate and urine samples of patients undergoing oxaliplatin therapy (21 , 22) .
Biotransformation Studies in Vivo.
Allen et al. (21
, 22)
have demonstrated that
oxaliplatin undergoes extensive biotransformation in cancer patients,
with evidence of nucleophilic substitution of the oxalate-leaving group
and dissociation of the platinum complex from the carrier ligand, DACH.
The major routes of biotransformation to active species is depicted in
Fig. 6
. Oxaliplatin was below the limit of detection in plasma
ultrafiltrate at the end of infusion (2 h) at 130
mg/m2 and could not be detected in urine. Up to
17 platinum-containing products were observed in the plasma
ultrafiltrate, the major one of which, in four of five patients,
corresponded by HPLC to monochloro-DACH platin (31–100% sample
platinum). Other putative DACH platinum complexes of dichloro
(2–8%), diaquo (2–26%), methionine (8–24%), monochlorocreatinine
(2–11%), and glutathione (12%) appeared to be present in plasma
ultrafiltrate. A number of unknown products were also observed
(21
, 22)
.
Up to 21 products were resolved by HPLC in urine, a number of which were characterized by mass spectrometry. These included dicreatinine (1–4% platinum dose), methionine (1–7%), monochloro (2%), monochlorocreatinine (1–20%), and monocreatinine (1–10%) DACH platins. In addition, glutathione DACH platin (2–18% dose) and a number of unidentified products were also resolved by HPLC (21 , 22) .
Preclinical cytotoxicity studies indicate that the monochloro-, dichloro-, and diaquo-DACH platin represent the principal cytotoxic platinum species in the systemic circulation, whereas the conjugated platinum complexes were devoid of cytotoxic activity (42) .
Platinum Elimination
Urinary and Fecal Elimination of Platinum.
The elimination of platinum occurs mainly in urine rather than in feces
(Table 5)
.
|
Between 2 and 12% of
the administered dose was excreted in urine as free DACH carrier
ligand.
Similar mass balance results have also been reported by other
investigators (19
, 28
, 30)
and are summarized in Table 5
.
PKs in Special Patient Populations
Platinum Clearance and Renal Function.
The clearance of platinum in patients with normal renal function and
moderate renal impairment has been investigated by Massari et
al. (35)
. Twenty-four patients were evaluated (10
with moderate renal impairment and 14 with normal renal function) after
a single dose of oxaliplatin at a dose of 130
mg/m2 given as a 2-h infusion. The median
creatinine clearance in the normal group was 78.00 (± 19.63) ml/min.
One patient in this group had a calculated creatinine clearance <60
ml/min but was still included in the normal group due to the absence of
any history of renal failure. The median creatinine clearance in the
renally impaired group was 42.20 (± 10.63) ml/min.
There was no statistically significant difference between the two groups with respect to ultrafilterable platinum Cmax. There was, however, a significant increase in AUC in patients with moderate renal impairment and a significant decrease in clearance of ultrafiltrate platinum (35) . Clearance in the group with moderate renal impairment was 14.23 ± 6.04 liters/h. This was significantly lower (P = 0.005) than clearance in the group with normal renal function (25.70 ± 8.53 liters/h). Although there was a significant decrease in the clearance of ultrafilterable platinum, no additional toxicity was observed in the renally impaired patients (35) .
Platinum Clearance.
Typically the clearance of ultrafilterable platinum has been shown to
range from 9.34 ± 2.85 to 13.3 liters/h at 130
mg/m2 (Table 4)
. The apparently higher clearance
at 85 mg/m2 (18.5 ± 4.71) and in the study
by Massari et al. (35)
quoted above is likely to be due to
underestimation of the AUC.
Renal clearance at 130 mg/m2 (4.66 liters/h) contributed to approximately half of the total clearance of platinum and was close to the average human GFR of approximately 7.5 liters/h. The clearance of ultrafilterable plasma platinum and platinum renal clearance was also significantly correlated with GFR (36) . These results indicate that glomerular filtration is a major mechanism of platinum elimination from the body after oxaliplatin administration.
Clearance of platinum from plasma and blood cells was relatively low (19 , 20) , which is probably a reflection of the covalent binding of platinum to these matrices.
Platinum Clearance and the Effect of Hepatic Function, Sex, and
Age.
A meta-analysis in 26 patients pooled from two studies
(n = 26 subjects) was performed by Graham et
al. (36)
to investigate the relationship between
hepatic function (baseline ALT) and ultrafilterable platinum
clearance. There was no statistically significant difference
(P = 0.507) in platinum clearance in patients with
normal ALT values (2–47 units/liter) or in patients with mild to
moderate elevations in ALT values (48–126 units/liter; Ref.
36
).
In the same meta-analysis, no statistically significant differences (P = 0.0657) were observed between males and females with respect to the clearance of ultrafilterable platinum (36) . Similarly, no statistically significant correlation (P = 0.618) was observed between the clearance of ultrafilterable platinum and age (26–72 years; Ref. 36 ).
Drug-Drug Interactions
Effect of Oxaliplatin on 5-FU Clearance.
The effect of oxaliplatin on the PKs of 5-FU has been studied in
18 patients with colorectal carcinoma (37
, 38)
. 5-FU was
administered to these patients according to the de Gramont regimen (200
mg/m2 leucovorin, 400 mg/m2
5-FU as an i.v. bolus injection on day 1 followed by 600
mg/m2 5-FU by 22 h of continuous infusion).
The study adopted a parallel group design (n = 9 patients per group) with or without a single infusion of oxaliplatin at 85 mg/m2. The PKs of 5-FU were compared in the presence and absence of oxaliplatin after 1–7 cycles of treatment with the combination.
Although an early interim analysis of the data in limited number of
patients reported a significant PK interaction between oxaliplatin and
5-FU (37)
, the final analysis of the full data set in 18
patients indicated no significant differences in 5-FU exposure in the
presence and absence of oxaliplatin (38
; Fig. 7
; Table 6
).
|
|
Effect of 5-FU on Platinum Clearance.
The effect of 5-FU on oxaliplatin PKs has not been studied directly;
however, comparison of platinum levels when oxaliplatin is combined
with 5-FU (weekly infusion regimen) show that oxaliplatin exposure in
the presence of 5-FU is within the normal range of the values derived
from single agent studies in the absence of 5-FU (30)
.
Drug-Drug Interaction Assessments In Vitro
CYP450 Interactions.
Oxaliplatin did not significantly inhibit (defined as a decrease in
enzyme activity to <70% of control rate) CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP3A4, CYP2D6, or CYP2E1. Therefore, metabolically
mediated drug-drug interactions of oxaliplatin on co-administered
drugs cleared by these CYP450 isoforms are not anticipated in the
clinic (32)
. Additionally, because the biotransformation
of oxaliplatin is not dependent on CYP450, induction or inhibition of
CYP450 activity by medications concomitantly administered with
oxaliplatin is not expected to affect platinum clearance.
Plasma Protein Binding Interactions.
Drug-drug interaction studies have been performed in
vitro, to investigate the ability of selected concomitant
medications, including erythromycin, salicylate, sodium valproate,
granisetron, and paclitaxel (Taxol), to displace oxaliplatin from
plasma proteins (44)
. Oxaliplatin (20 µg/ml) was
incubated at for 6 h with human serum protein in the presence of
erythromycin (7 µg/ml), salicylate (300 µg/ml), sodium valproate
(100 µg/ml), granisetron (100 ng/ml), and paclitaxel (5 µg/ml). Any
displaced platinum was then assayed in plasma ultrafiltrate by FAAS.
No significant displacement of platinum from plasma protein was observed with any of the concomitant medications tested, with the exception of a small (2.85%) increase in free platinum concentrations in the presence of erythromycin (44) . This small increase is not considered to be clinically significant, and no protein binding displacement reactions are anticipated in patients.
Comparative PKs of Oxaliplatin, Cisplatin, Carboplatin, and Tetraplatin
The comparative PKs of oxaliplatin, tetraplatin, cisplatin, and
carboplatin are presented in Table 7
. The PKs of platinum complexes are
determined by two major factors. First, the stability of the leaving
ligand largely determines the chemical reactivity and intrinsic
cytotoxicity of the complex. Second, the nature of the carrier ligand
may influence the tissue distribution characteristics of the molecule.
These two factors combined will determine the unique chemical
reactivity and disposition properties of a given platinum complex.
Among the most striking differences between the DACH platin complexes
compared to cisplatin and carboplatin are the differences in the volume
of distribution from plasma ultrafiltrate. Oxaliplatin and tetraplatin
have very large volumes of distribution (582 and 378 liters) compared
to 19.2 and 17.0 liters for cisplatin and carboplatin, respectively
(Table 7)
. This observation implies that
the DACH moiety may confer some advantages in terms of enhanced tissue
penetration that may be due altered cell membrane permeability. This
hypothesis is supported by the observation that oxaliplatin accumulates
more readily into erythrocytes compared to cisplatin and carboplatin, a
feature that cannot be explained solely on the basis of chemical
reactivity and covalent binding of platinum. To date, however, no
direct measurements of platinum concentrations in normal or tumor
tissue have been made after oxaliplatin administration to substantiate
this hypothesis.
|
Conclusions
The PKs of unbound platinum in plasma ultrafiltrate after oxaliplatin administration are typically triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252–273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (AUC0–48) was moderate to low (33 and 5%, respectively). Platinum bound irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Erythrocytes did not serve as a reservoir for platinum in the systemic circulation, and accumulation of platinum in blood cells is not considered to be of clinical significance. Platinum was rapidly cleared from plasma ultrafiltrate (9.34–18.5 liters/h) at a rate that was similar to or exceeded the average human GFR (7.5 liters/h). The renal clearance of platinum significantly correlated with GFR, indicating that renal filtration is a major mechanism of platinum clearance. Tissue distribution is also an equally major mechanism of platinum elimination from systemic circulation.
Clearance of ultrafilterable platinum was decreased in patients with moderate renal impairment; however, there was no increase in drug toxicity. The effect of severe renal impairment on platinum clearance and toxicity is unknown. There was no significant effect of age, sex, or moderate hepatic impairment on the clearance of ultrafilterable platinum. Oxaliplatin underwent rapid and extensive nonenzymatic biotransformation in plasma ultrafiltrate and urine in vitro and in vivo. There was no evidence of CYP450-mediated metabolism in vitro. Up to 17 platinum-containing products were observed in plasma ultrafiltrate samples, including several putative cytotoxic species (including monochloro-, dichloro-, and diaquo-DACH platin). A number of noncytotoxic products (methionine, monochlorocreatine, and glutathione DACH platins), together with some unknown products, were also observed. Urinary elimination (53.8 ± 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 ± 1.9% of the administered dose 5 days postadministration. No significant PK interaction between oxaliplatin, 5-FU, and CPT-11 have been observed in patients. Oxaliplatin did not inhibit CYP450 isoenzymes in vitro, and platinum was not displaced from plasma proteins by selected concomitant medications. No metabolism-based drug-drug interactions or plasma protein binding displacement interactions are therefore anticipated in patients.
Analysis of platinum PKs after oxaliplatin, tetraplatin, cisplatin, and carboplatin administration reveals marked differences in the platinum disposition characteristics between the drugs. This may be attributable to differences in the stability of the various leaving ligands, which in turn determine the chemical reactivity of the complex. In addition, the nature of the various carrier ligands also appears to profoundly alter the disposition characteristics of platinum, with the DACH platinum species exhibiting substantially higher volumes of distribution compared to cisplatin and carboplatin.
In conclusion, these PK, biotransformation, mass balance, and drug-drug interaction studies provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition in observed patients.
ACKNOWLEDGMENTS
We thank the following for their invaluable contributions and critical review of this work: J. Allen, J. Firth, J. G. Morrison, S. Woolfrey, S. McDougall, G, Shackleton, R. Crane, Jr., J. Newton, W. Brian, J. Brandl, S. Bernard, J-F. Thiercelin, J. Oppermann, R-H. Charollais, P. Rigaudy, T. Pearce, M. Boisdron-Celle, S. Joel, J. L. Missett, D. Papamichael, P. Allain, D. Cunningham, and S. Chaney.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should be
addressed, at Department of Clinical Pharmacokinetics and Drug
Metabolism, Sanofi-Synthelabo, 9 Great Valley Parkway, Malvern,
PA 19355. Phone: 610-889-6025; Fax: 610-889-6356. 
2 The abbreviations used are: PK, pharmacokinetic;
AUC, area under the curve; CI, confidence interval; CYP 450, cytochrome
P450; DACH, diaminocyclohexane; FAAS, flameless atomic
absorption spectroscopy; 5-FU, 5-fluorouracil; GFR, glomerular
filtration rate; HPLC, high-pressure liquid chromatography;
ICPMS, inductively coupled plasma mass spectrometry; ALT, alanine
transaminase; CPT-11, irinothecan.
Received 7/ 8/99; revised 12/14/99; accepted 12/20/99.
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, individual platinum
concentrations;
, trough platinum concentrations
