You are on page 1of 17

Dosage Adjustment for Cytotoxics in Renal

Impairment
November 2003

Produced by Susanna Daniels (April 2001)


Updated by Sumantha Gabriel & Susanna Daniels (UCL Hospitals NHS Trust)
Dosage Adjustment for Cytotoxics in Renal Impairment

This table is a guide only. Pharmacokinetic, Summary of Product Characteristics (SPC), relevant pharmaceutical company data and various references
have been reviewed for each drug. From this information, a recommendation has been suggested. Input of the full clinical picture of the patient should
always be taken into account. As limited data is available, the scope of the document applies to adult data. If paediatric data is obtainable, this has been
included. If a patient is following a specific clinical trial or protocol, it is advisable to follow the associated dose modifications.

The BNF (Edition 46) states:


Mild renal impairment: GFR 20-50ml/min; Serum creatinine 150-300 mol/litre
Moderate renal impairment: GFR 10-20ml/min; Serum creatinine 300-700 mol/litre
Severe renal impairment: GFR <10ml/min; Serum creatinine > 700 mol/litre

Drug Pharmacokinetics Available Information Recommendation

Alemtuzumab t1/2 23 30 hours. SPC No studies have been conducted in patients with renal impairment Clinical Decision
Serum concentration rise Treatment is not recommended.
corresponds with reduction in
malignant lymphocytosis. Different
pharmacokinetic properties may be
related to different tumour burden
and distribution.

Amsacrine Amsacrine is extensively SPC for patients with impaired renal function, reduce dose by 20-30% (to 60- If CrCl < 60ml/min, reduce dose by
metabolised in the liver. The 75mg/m2 per day) 20-30%.
principal metabolites, via Goldshield no information.
microsomal oxidation, are much
more cytotoxic than the parent
drug. Excretion is via the bile.
>50% excreted in faeces within 2
hours; 35% in urine11

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 2 of 2
Drug Pharmacokinetics Available Information Recommendation

Bleomycin t½ 2-4 hours. SPC If creatinine 177-354 mol/L, give 50% dose. If creatinine >354 mol/L, CrCl (ml/min) Dose
Rapid distribution to body tissues further reduction is necessary. The rate of excretion is highly influenced by
(highest concn in skin, lungs, renal function; concentrations in plasma are greatly elevated if usual doses are >50 100%
peritoneum & lymph). Inactivation given to patients with renal impairment with only up to 20% excreted in 24 10-50 75%
takes place primarily in the liver. ~ hours. Observations indicate that it is difficult to eliminate bleomycin by <10 50%
2/3 of drug is excreted unchanged dialysis.
in the urine, probably by glomerular Kyowa Hakko when GFR <30ml/min, bleomycin excretion decreases
filtration. rapidly, causing blood concn to rise. Patients with abnormal kidney function
tend to develop lung dysfunction.
Faulding suggested dose modification schedule: CrCl 10-50ml/min 75%
dose. CrCl < 10ml/min, give 50% dose.

Busulfan The mean elimination t½ is 2.57hrs. SPC no information. No dose reduction necessary.
Extensive hepatic metabolism to at Glaxo Wellcome although very little unmetabolised drug is excreted in the
least 12 metabolites. After low and urine, a complex range of metabolites are excreted by this route. The
high doses, 1 & 2% respectively of administration of high-dose busulphan has been evaluated in 15 patients with
unchanged drug is excreted in the multiple myeloma (4 had CrCl < 30ml/min) with no problems.5
urine. The majority of an oral dose BC Cancer Agency no dose reduction required in patients with renal
is excreted in the urine as failure.11
methanesulfonic acid, an inactive
metabolite.

Capecitabine Extensive absorption (~70%) after SPC capecitabine is contra-indicated in patients with severe renal impairment CrCl (ml/min) Dose
food intake. Metabolism is first in (CrCl <30 ml/min) The incidence of grade 3-4 toxicities in patients with
the liver and then in the tumour. Up moderate renal impairment (CrCl 30-50 ml/min) is increased. An initial dose of 51-81 100%
to 96%11dose is recovered in the 75% is recommended. In patients with mild renal impairment (CrCl 51- 30-50 75%
urine. Terminal t½ = 0.75 hours. 81ml/min), no adjustment of the starting dose is recommended. Careful <30 CI
monitoring and prompt treatment interruption is recommended if the patient
develops a grade 2, 3, or 4 adverse event, followed by the appropriate dose
adjustment.
Roche as SPC

Carboplatin There is little, if any, true SPC dose reduce with renal impairment and monitor haematological nadirs Dose using Calvert equation:
metabolism of carboplatin. and renal function. Myelosuppression is closely related to renal clearance. Dose = AUC(25 + GFR)
Excretion is primarily by Carboplatin is contra-indicated with CrCl <20ml/min.
glomerular filtration in urine, with Faulding CrCl >40ml/min, max dose = 400mg/m2 CI if CrCl <20ml/min
most of the drug excreted in the CrCl 20-39ml/min, max dose = 250mg/m2
first 6hrs. ~32% dose is excreted Dialysis extensively removed by haemodialysis11 Dialysis extensively removed by
unchanged. haemodialysis11
Terminal t½ ~ 6 days.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 3 of 3
Drug Pharmacokinetics Available Information Recommendation

Carmustine Partially metabolised to active SPC no information. CrCl (ml/min) Dose


species by liver microsomal BMS very little information. Clinical decision based on the haematological
enzymes, which have a long t½. It response to previous doses, monitoring blood counts. 60 80%
is thought that the antineoplastic Kintzel et al2 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl of 45 75%
activity may be due to metabolites. 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, carmustine is not 30 50%
~60-70% of the total dose is recommended 15 25%
excreted in the urine in 96hrs and BC Cancer Agency - for creatinine clearance <12 mL/min give 25-50% of
~10% as respiratory CO2. dose.11 Dialysis no dose adjustment
Terminal t½ ~ 1 hour. required.
Dialysis (BMS) Carmustine is not dialysed. Dose adjustment is not required
in patients under renal replacement therapy. Includes CAPD, HD, continuous
arterio-venous/veno-venous haemodiafiltration18

Chlorambucil Good oral absorption - absorption SPC monitor patients with evidence of impaired renal function as prone to No dose reduction necessary,
slowed and decreased by 10-20% if additional myelosuppression associated with azotaemia. however, monitor patients carefully,
ingested with food. Metabolism Glaxo Wellcome very little information. Renal function does not appear to as they are more prone to
predominantly in liver via hepatic affect the elimination rate. Chlorambucil is unlikely to be dialysed. myelosuppression.
microsomal enzyme oxidation
system. <1% excreted unchanged Dialysis unlikely to be dialysed.
in the urine. t½ = 2 hours.
Chlormethine Following intravenous injection, it SPC - no information available No information available.
(Mustine) is rapidly converted to a reactive Probably no dose reduction
ethyleneimmonium ion. Usually necessary.
disappears from the blood within Clinical decision
approximately ten minutes. t1/2 15
minutes.11 Less than 0.01% of drug
is excreted unchanged in the urine.
50% excreted in the urine as
metabolites after 24 hours.11
Cisplatin Non-enzymatically transformed SPC cisplatin induces nephrotoxicity, which is cumulative. It is therefore GFR (ml/min) Dose
into multiple metabolites.11 There is contra-indicated in patients with renal impairment. >60 100%
good uptake of cisplatin in the Faulding - Kintzel et al2 suggest for CrCl of 60ml/min; use 0.75 fraction of 50-60 75%
kidneys, liver and intestine. dose, for CrCl of 45ml/min, use 0.5 fraction of dose, for CrCl of 30ml/min, 40-50 50%
Distributes into third spaces such as cisplatin is contra-indicated. <40 CI
ascites and pleural fluid.11 The Bennett et al8 GFR >50mls/min 100% dose; GFR 10-50mls/min 75% dose Consider carboplatin if GFR
elimination of intact drug and GFR <10mls/min 50% dose <40ml/min
metabolites is via the urine. In the Haemodialysis Dialysed. Give 50% dose8 Conflicting information. Where GFR
first 24hrs 20-80% is excreted. NB. There is experience of using the same dose as the GFR. It should be is less than 40mls/min - clinical
noted, however, that there is no evidence for this practice. decision.

Dialysis give 50% dose.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 4 of 4
Drug Pharmacokinetics Available Information Recommendation

Cladribine Pro-drug - activated by intracellular SPC acute renal insufficiency has developed in some patients receiving high Lack of information available.
phosphorylation. The nucleotide doses of cladribine. There is inadequate data on dosing of patients with renal Clinical decision
that is formed accumulates in the insufficiency.
cell and is incorporated into the Janssen-Cilag very limited information available. In a small study (n=9), it
DNA. ~20% was recovered was found that less than 30% of cladribine was excreted in the urine and less
unchanged in the urine. than 10% was excreted as metabolite.

Cyclophosphamide Pro-drug converted by hepatic SPC not recommended in patients with a creatinine >120 mol/L. GFR (ml/min) Dose
microsomal enzymes to alkylating Asta Medical - Patients with impaired renal function have been reported to >50 100%
metabolites (great interpatient show an increase in metabolite concn. 10-50 75%
variability in metabolism). Cyclophosphamide and its metabolites can be eliminated by haemodialysis <10 50%
Excretion primarily renal. 30% is Availability of mesna in the urinary tract depends on renal function. Clinical decision consider whether
excreted as unchanged drug. t½ is Lam et al 25 If CrCl > 10 ml/min, give 100% dose. patient is being treated with high dose
4-10 hours in adults and 1-6.5 hours treatment.
in children. Dialysis - Baxter (Prev Asta Medical) it is known that cyclophosphamide
and its alkylating metabolites can be eliminated by dialysis16,20,21,22,23
In case of complete anuria, neither cyclophosphamide, nor its metabolites
should appear in the urinary tract. The use of mesna concomitantly may
therefore be unnecessary in anuric patients.
If there is any risk of cyclophosphamide or its metabolites entering the urinary
tract, mesna should probably be given to prevent urothelial toxicity. It should be
noted that complete anuria is extremely rare.

Cytarabine Cytarabine is concentrated in the SPC dose reduction does not appear to be necessary in patients with impaired No dose reduction necessary
liver. A major fraction of a dose is renal function. The human liver apparently detoxifies a substantial fraction of High Dose 1- 3g/m2:
inactivated by cytidine deaminase the administered dose.
in the liver and other body tissues. Faulding when using high dose cytarabine (1-3g/m2) reduced doses should be GFR (ml/min) Dose
After 24hrs, 80% dose has been considered in patients with renal impairment3
eliminated either as the inactive >60 60%
metabolite or as unchanged >45 50%
cytarabine, mostly in the urine, but <30 CI
some in the bile.

Dacarbazine Dacarbazine (DTIC) is assumed to SPC no information. CrCl (ml/min) Dose


be inactive. Microsomal Bayer no information.
metabolism in the liver produces Faulding as the drug is excreted 50% unchanged in the urine by tubular 60 80%
main metabolite; AIC. ~50% DTIC secretion, impairment of renal function is likely to necessitate a change in 45 75%
is renally cleared. ½ of this is dosage. 30 70%
unchanged DTIC & ~ ½ is AIC. Kintzel et al2 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl of
DTIC is renally tubularly secreted, 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, use 0.7 fraction of
rather than glomerularly filtered. dose.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 5 of 5
Drug Pharmacokinetics Available Information Recommendation

Dactinomycin 15% eliminated by hepatic SPC no information. Clinical decision


metabolism. ~30% of the dose was MSD - no information.
recovered in the urine and faeces in
1week. The terminal plasma t½ ~
36hrs.

Daunorubicin Daunorubicin is rapidly taken up by SPC a dose reduction is recommended in patients with impaired hepatic or Creatinine Dose
the tissues, especially by the renal function. / mol/L
kidneys, liver, spleen and heart. See recommendations
Subsequent release from of drug Aventis as SPC <105 100%
and metabolites is slow (t½ ~ 105-265 75%
55hrs). Rapidly metabolised in the >265 50%
liver & the major metabolite,
daunorubicinol is also active. It is
excreted slowly in the urine, mainly
as metabolites with 25% excreted
within 5 days. Biliary excretion
accounts for 40% elimination.

Docetaxel Cytochrome P-450 mediated SPC no information No dose reduction necessary.


metabolism. In animal studies Aventis no dose adjustment necessary.
distributed to all tissues and organs 1 major and 3 minor metabolites have been identified and these are excreted in
except the brain.11 6% and 75% of the faeces.
the dose is excreted via the renal
and faecal route respectively within
7 days. Terminal t½ = 2.5 hours.

Doxorubicin Mainly metabolised in the liver. SPC no information Dose reduce in severe renal
Rapidly cleared from plasma and Pharmacia Yoshida et al7 have shown that the AUC of doxorubicin and impairment. Clinical decision.
slowly excreted in the urine and doxorubicinol (active metabolite) is significantly higher in patients with renal
bile (50% of drug recoverable in the failure. This study also suggests special attention should be paid to
bile or faeces in 7 days). haemodialysis patients receiving digoxin
Mayne no information.

Epirubicin Mainly metabolised in the liver. SPC Moderate renal impairment does not appear to require a dose reduction Dose reduce in severe impairment
Slow elimination through the liver in view of the limited amount excreted by this route. only. Clinical decision.
is due to extensive tissue Pharmacia little information.
distribution. 27-40% biliary
excretion. Urinary excretion
accounts for ~10% of dose in 48hrs.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 6 of 6
Drug Pharmacokinetics Available Information Recommendation

Etoposide Liver metabolised, yielding inactive SPC Etoposide reaches high concn in the liver and kidney CrCl (ml/min) Dose
metabolites. ~45% of an BMS Creatinine clearance is the strongest predictor of etoposide clearance. 60 85%
administered dose is excreted in the US prescribing information suggest a 25% dose reduction for GFR between 15 45 80%
urine, 29% being excreted 50 ml/min.4 Subsequent dosing should be based on patient tolerance and clinical 30 75%
unchanged in 72 hrs. Upto 16% effect. A further dose reduction should be considered with GFR<15ml/min. <15 50%
recovered in the faeces. Kintzel et al2 suggest for CrCl of 60ml/min; use 0.85 fraction of dose, for CrCl
of 45ml/min, use 0.8 fraction of dose, for CrCl of 30ml/min, use 0.75 fraction of Subsequent doses should be based on
dose. clinical response.
Haemodialysis Holthius et al14 reported comparable pharmacokinetics in
patients receiving haemodialysis for doses of etoposide up to 127mg/m2 in Haemodialysis start at reduced
relation to patients with normal renal function. dose and increase according to
Sauer et al15 and Brindley et al16 found that etoposide is not removed by clinical response.
dialysis.

Fludarabine Rapidly dephosphorylated in SPC If CrCl 30-70ml/min, give 50% dose and close haematological CrCl (ml/min) Dose
plasma to 2-F-ara-ATP, which is monitoring should be used to monitor toxicity. If CrCl <30 ml/min, fludarabine
necessary for cellular uptake11~ is contra-indicated. >70 100%
60% of an administered dose is Schering as SPC 30-70 50%
excreted in the urine within 24hrs. <30 CI

Fluorouracil Fluorouracil is distributed through SPC Fluorouracil should be used with caution in patients with reduced renal Consider dose reduction in severe
the body water. Activated in target or liver function or jaundice. renal impairment only.
cells, catabolized in liver - most of Faulding Bennett et al8 suggested that no dose adjustment is needed in renal
dose (80%) eliminated by liver11 impairment.
60-80% is excreted as respiratory
CO2 , 2-3% by biliary system11
Following a single IV dose, ~15%
dose is excreted unchanged in the
urine.

Gemcitabine Rapid metabolism by cytidine SPC Use with caution in patients with impaired renal function. CrCl>30ml/min standard dosing
deaminase in the liver, kidney, Lilly Since gemcitabine is extensively metabolised by various tissues, mild to CrCl<30ml/min consider dose
blood and other tissues. The active moderate renal insufficiency would not be expected to significantly affect its reduction clinical decision.
intracellular metabolites have not clearance, although there is a possibility of accumulation of the inactive
been detected in plasma or urine. metabolite, dFdU. Lilly investigated the PK in 18 patients with renal Haemodialysis pre dose and 48
Urinary excretion of parent drug insufficiency and found that there was no significant difference between hours post dose.
and inactive metabolite (dFdU) patients on the basis of their GFR (GFR ranged from 30ml/min upwards).
accounts for 99%. Haemodialysis conventional intermittent haemodialysis should be performed
Terminal t½ is ~1 hour this before a weekly dose and again some 48 hours later. Provided this is carried out
increases if the drug is administered the patient should not face excess toxicity.
over a longer period.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 7 of 7
Drug Pharmacokinetics Available Information Recommendation

Hydroxycarbamide After oral administration, SPC- use with caution in patients with marked renal dysfunction. CrCl (ml/min) Dose
(Hydroxyurea) hydroxyurea is readily absorbed BMS
from the GI tract. 50% hepatically Kintzel et al2 suggest for CrCl of 60ml/min; use 0.85 fraction of dose, for CrCl 60 85%
metabolised11. Peak plasma concn of 45ml/min, use 0.8 fraction of dose, for CrCl of 30ml/min, use 0.75 fraction of 45 80%
are reached by 2hrs. 50% of a dose dose. 30 75%
recovered in urine within 12 hours, Bennett et al3 suggest reducing the dose by half in patients with GFR 10 50%
mainly as intact drug. The rest is <10ml/min.
excreted as carbon dioxide via the Dialysis hydroxyurea is probably dialysed, patients should be dosed with 20%
Dialysis reduce dose by 20% and
lungs or via the urine as urea11 t½ normal dose and titrate to response.18
titrate according to response.
= 2-4 hours.
Idarubicin Oral idarubicin has rapid but erratic SPC in a number of Phase III clinical trials, treatment was not given if Cr Creatinine Dose
absorption, about 30% >177 mol/L. For other anthracyclines, 50% dose reduce if Cr in range 106- / mol/L
bioavailability. Extensive liver11 177 mol/L. Contra-indicated in severe renal impairment.
metabolism to idarubicinol which Pharmacia some studies have suggested that patients with Cr levels up to <100 100%
has equipotent activity and a much 350 mol/L can be treated with oral idarubicin without dose modification 100-175 50%
longer t½ than idarubicin (50 vs >175 clinical decision
18hrs). Elimination is via the
hepatobiliary and renal system
mostly as idarubicinol. 17% (IV) /
8% (oral) is recovered in the faeces
over 5 days and 16% (IV) / 5%
(oral) is recovered in the urine over
4 days.

Ifosfamide Pro-drug converted by hepatic SPC not recommended in patients with a creatinine >120 mol/L. GFR (ml/min) Dose
microsomal enzymes to alkylating Asta Medical Dose reduction schedules established for cyclophosphamide >60 100%
metabolites. Excretion primarily (which has similar metabolic PK parameters). Ifosfamide is known to be more 40-59 70%
renal. ~80% dose excreted as nephrotoxic than cyclophosphamide + has a CNS toxicity profile. <40 clinical decision
parent compound. Availability of mesna in the urinary tract depends on renal function.
Serum t½ ranges between 4-8hrs. Euro-EWING protocol Ifosfamide 9 g/m2 administered per course. Protocol SPC states that if creatinine
suggests to treat with 100% dose if GFR 60 ml/min. If GFR = 40-59 ml/min, >120 mol/L, ifosfamide is not
give 70% dose. If GFR <40 ml/min, use cyclophosphamide instead (1500 recommended.
mg/m2).

Imatinib High oral bioavailability (98%). SPC Imatinib and its metabolites are not significantly excreted via the kidney. Dose reduction probably not
Main circulating metabolite is N- Since renal clearance of imatinib is negligible, a decrease in total body required.
demethylated piperazine derivative. clearance is not expected in-patients with renal insufficiency, However, in
Catalysed by cytochrome P450 severe renal insufficiency caution is recommended.
CYP3A4
Mainly hepatic metabolism 68%
excreted in faeces and 13% in urine
in 7 days. t½ = 18 hours.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 8 of 8
Drug Pharmacokinetics Available Information Recommendation

Irinotecan Metabolism is primarily hepatic, SPC not recommended in patients with impaired renal function as studies in No dose reduction needed, however
where irinotecan is rapidly this population have not been done. use with caution as no information in
converted to active metabolite SN- Aventis as above this setting.
38 by hepatic carboxylesterase Haemodialysis - Patient treated with 80mg/m2 without severe side effects.
enzymes. Haemodialysis with irinotecan seems feasible. May be advisable to start at a
Excretion is predominantly biliary low dose e.g. 50mg/m2 and escalate slowly if tolerated. 14
64% excreted in faeces. The mean
24hr urinary excretion of irinotecan
and SN-38 (its active metabolite)
was 19.9% and 0.25% respectively.

Liposomal Pharmacokinetic profile SPC no information. Very little information.


Daunorubicin significantly different to Gilead Sciences From American prescribing information. Where serum Cr If Cr >265 mol/L, give 50% normal
daunorubicin, with a longer t½ and >265 mol/L give 50% normal dose. dose.
a 200-400-fold reduction in volume Monitor toxicities in particular cardiotoxicity. As excretion is mostly through
of distribution. Metabolism bile, special care must be taken with hepatic dysfunction.
appeared not to be significant at
lower doses. Clearance of the
liposomes may be mediated by the
reticuloendothelial cells with a
selective enhancement of uptake in
tumour cells. Anthracyclines are
excreted mostly through bile.
Liposomal The plasma levels are 10-20-fold SPC as doxorubicin is metabolised by the liver and excreted in the bile, dose No dose reduction needed.
Doxorubicin higher than equivalent doxorubicin modifications should not be required for liposomal doxorubicin.
doses. There is a preferential Schering-Plough no further information
retention of the drug in the
reticuloendothelial system, such as
liver, spleen and lungs. It appears
that the liposomal preparation
serves as a slow-release preparation
for free doxorubicin.

Lomustine Relatively rapid and complete oral SPC no information CrCl (ml/min) Dose
absorption, followed by first pass Medac no information.
metabolism. Part of lomustine BC Cancer Agency if CrCl 12-48 ml/min, give 75% previous dose and if >60 100%
metabolism is mediated through CrCl < 12 ml/min, give 25-50% previous dose. 45 - 60 75%
hepatic microsomal enzymes. Kintzel et al2 suggest for CrCl of 60ml/min; use 0.75 fraction of dose, for CrCl 30 - 45 50%
Metabolites predominantly excreted of 45ml/min, use 0.7 fraction of dose, for CrCl of 30ml/min, lomustine is not <30 not
by kidneys; 10% excreted as CO2 recommended. recommended
and <5% in faeces.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 9 of 9
Drug Pharmacokinetics Available Information Recommendation

Melphalan Incomplete and variable oral SPC Clearance, although variable, is decreased in renal impairment. GFR 30-50ml/min, give 50% dose.
absorption - 25-89% post oral dose; For conventional IV doses (16-40mg/m2) & moderate severe impairment,
AUC decreased by 39% when taken reduce initial dose by 50% and subsequent dosage determined by For GFR <30ml/min, clinical
with food. haematological suppression. decision. Some sources suggest that
Spontaneous degradation rather For high IV doses (100-240mg/m2) and GFR 30-50ml/min, reduce dose by 50% not necessary to withhold high dose
than enzymatic metabolism. Adequate hydration and forced diuresis are also necessary. therapy dose may be split on to 2
Percentage of dose excreted in the High dose is not recommended in patients with GFR<30ml/min. consecutive days.
urine as active or toxic moiety Glaxo Wellcome as above. Other authors have suggested that it may not be
ranges from 11-93%. 20-50% absolutely necessary to withhold high-dose from patients with severe renal
excreted in the faeces within 6 impairment as kidneys not a major influence on melphalan pharmacokinetics.
days. t½ ~ 1.5-2hrs. Tricot et al25 Addressed safety of autotransplants in patients with a GFR
<40ml/min. The dose of 200mg/m2 was divided into two doses
(100mg/m2/day) and given on two consecutive days. This schedule did not
adversely affect the incidence of severe mucositis or overall survival, however,
it was associated with longer durations of fever and hospitalisation.

Mercaptopurine Absorption of an oral dose is SPC monitor renal function in the elderly. Clinical decision
incomplete, averaging ~50%. This Glaxo Wellcome no information. Consider increasing dosing interval
is largely due to first pass With renal impairment, the use of the following dosing intervals has been as follows:
metabolism in the liver (less when suggested: CrCl of 50-80ml/min 24-36hrs
given with food). There is 24-36hrs for CrCl of 50-80ml/min, and 48hrs for CrCl of 10-50ml/min.9 CrCl of 10-50ml/min 48hrs
enormous inter-individual
variability in absorption, which can
result in a 5-fold variations in AUC.
It is extensively metabolised (by
intracellular activation). At
conventional doses clearance is
primarily hepatic. Renal clearance
may become important at high
doses.11 t½ = 1-3 hrs (PO) and 0.3-
1 hr (IV).

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 10 of 10
Drug Pharmacokinetics Available Information Recommendation

Methotrexate The dose is well absorbed at doses SPC (Faulding) impaired renal function is usually a contra-indication. CrCl (ml/min) Dose
< 30mg/m2 bioavailability is SPC (Wyeth) profound renal impairment is a contra-indication. Use with
decreased by food and milk. extreme caution in patients with renal impairment. >80 100%
Metabolism is via liver and Wyeth Renal clearance correlates with CrCl. Methotrexate t½ is inversely 60 65%
intracellular metabolism to related to CrCl. 45 50%
polyglutamated products.11 Kintzel et al2 - suggest suggest for CrCl of 60ml/min; use 0.65 fraction of dose, <30 CI
The drug is excreted primarily by for CrCl of 45ml/min, use 0.5 fraction of dose, for CrCl of 30ml/min,
the kidneys (>90%), although small methotrexate is not recommended.
Haemodialysis8 Give 50% dose.
amounts via the bile. Clearance is Drug Prescribing in Renal Failure8 GFR >50ml/min use 100% dose; GFR 10-
higher in children than in adults. t½ 50ml/min use 50% dose; GFR<10ml/min avoid.
~ 8 hrs. Haemodialysis8 Give 50% dose.

Mitomycin C Pro drug activated in vivo.11 SPC no information on dose adjustment. Severe renal toxicity has GFR (ml/min) Dose
Metabolism is predominantly in the occasionally been reported after treatment and renal function should be
liver. The rate of clearance is monitored before each course. >10 100%
inversely proportional to the Kyowa Hakko no further information.
maximal serum concn, due to Fischer D et al10 suggest the following: <10 75%
saturation of the degradative For GFR 10-60ml/min, use 75% dose, for GFR <10ml/min, use 50% dose.
pathways. ~10% is excreted The Renal Drug Handbook18 GFR >10ml/min use 100% dose GFR Consider a dose reduction for high
unchanged in the urine. Since <10ml/min use 75% dose doses of mitomycin when GFR 10-60
metabolic pathways are saturated at Dialysis18 Haemodialysis and CAPD dose as in GFR <10mls/min (75% dose) mL/min.
low doses, the % dose excreted in
the urine increases with increasing Dialysis18 Haemodialysis and
dose. CAPD dose as in GFR <10mls/min
(75% dose)

Mitoxantrone Extensive metabolism in the liver. SPC no information No dose reductions necessary.
Excretion is predominantly bile and Wyeth Dose reductions appear to be unnecessary in patients with reduced
faeces. 5-10% of dose is excreted renal function. The principal dose-limiting side effect is myelosuppression,
in the urine within 5 days. which should be monitored. Mitoxantrone does not appear to be eliminated by
haemodialysis and dose adjustments are not needed in such patients.
Dialysis extensively tissue bound therefore unlikely to be eliminated by
haemodialysis or peritoneal dialysis. Dose adjustments may not be needed in
patients undergoing this procedure23

Oxaliplatin In vitro, there is no evidence of SPC Oxaliplatin has not been studied in patients with severe renal impairment Moderate renal impairment treat at
cytochrome P450 metabolism. (<30ml/min). In patients with moderate renal impairment, treatment may be normal dose, and monitor renal
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 11 of 11
Drug Pharmacokinetics Available Information Recommendation

Extensive nonenzymatic initiated at the normally recommended dose. Consider risk/benefit ratio. There function. Dose adjust according to
biotransformation occurs. Platinum is no need to dose reduce in patients with mild renal dysfunction. toxicity.
is excreted mainly by renal Sanofi Massari C et al6 looked at patients with normal and impaired (27-
excretion and tissue 57ml/min) renal function. Data showed the same plasma levels between the 2 CrCl <20m/min dose reduce
distribution,while platinum groups, and the clearance of both total and free platinum as well as AUC
metabolites are mainly by renal correlated with the CrCl. Toxicities were similar in the 2 groups. Haemodialysis it is not anticipated
excretion. By day 5, ~54% of the Takimoto CH et al24 Data found to support the recommendation that dose that dialysis treatment during therapy
total dose was recovered in the reductions of single-agent oxaliplatin are not necessary in patients with a CrCl would cause any problems.
urine and <3% in the faeces. greater than 20ml/min (dose based on 130mg/m2 every three weeks).
Haemodialysis (Sanofi) it is not anticipated that dialysis treatment during
oxaliplatin therapy would cause any problems.

Paclitaxel Hepatic metabolism and biliary SPC no recommendations No dose reductions necessary.
clearance is the principal BMS within 24-48 hrs following administration, <10% of the dose appears in
mechanism for disposition. Mean the urine. In dialysis patients, full dose has been given (on non-dialysis days)
values for cumulative urinary with a typical toxicity profile.
recovery of unchanged drug ranged Paclitaxel chemotherapy is efficacious and feasible for patients undergoing
from 1.3 to 12.6% of the dose, haemodialysis (NB study was carried out in ovarian cancer at 150mg/m2).13
indicating extensive non-renal
clearance.

Pentostatin Only a small amount is SPC 2 patients with impaired CrCl 50-60 ml/min achieved complete response CrCl Dose
metabolised. It is primarily without unusual adverse events when treated with 2mg/m2 (50% dose). Given (ml/min)
excreted unchanged by the kidneys limited data, if CrCl <60 ml/min, pentostatin is contra-indicated.
- 30 90% excreted by kidneys Wyeth no further information. >60 100%
within 24 hours11 50-60 50%
<50 not recommended

Procarbazine After oral absorption, the drug SPC caution advisable in patients with renal dysfunction. Lack of available information.
appears to be rapidly and Cambridge Labs. no further information. If serum creatinine >177 mol/L, give
completely absorbed. Procarbazine With serum creatinine >177 mol/L, doses should be substantially reduced.9 50% dose.
is metabolised by microsomal
enzymes in the liver to an active For severe renal impairment not
alkylating agent. After 24hrs up to recommended.
70% of a dose is recovered in the
urine.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 12 of 12
Drug Pharmacokinetics Available Information Recommendation

Raltitrexed Not metabolised. 40-50% is SPC see recommendations CrCl ml/min Dose Interval
excreted unchanged in the urine. AstraZeneca as SPC
15% of dose is excreted in the >65 100% 3 wkly
faeces over a 10-day period. Active 55-65 75% 4 wkly
tubular secretion may contribute to 25-54 50% 4 wkly
the renal excretion11 <25 0% -

Rituximab Mean serum t1/2 increases with dose SPC no information Probably no dose reduction
and repeated dosing - 76.3 hours Roche no information necessary.
after 1st infusion and 205.8 hours
after 4th infusion.
Detectable in body for 3-6 months.

Temozolomide Temozolomide is rapidly and SPC no data with renal dysfunction. Analysis of population pharmacokinetic Probably no dose reduction
completely absorbed with 100% data revealed that plasma temozolomide clearance was independent of age and necessary.
bioavailabiltiy. Tissue distribution renal function. It is unlikely that dose reductions are required in patients with
is extensive11. t½ is ~1.8hrs. The severe renal dysfunction.
major route of elimination is renal. Schering-Plough no further information.
~5-10% is excreted unchanged and
the remainder as metabolites.

Thioguanine Variable and incomplete oral SPC Consideration should be given to reducing the dosage in patients with Consider dose reduction, but no
absorption with 14-46% impaired hepatic or renal function. formal recommendations.
bioavailability. Extensive Glaxo Wellcome very little information.
metabolism in the liver and other
tissues to several active and
inactive metabolites. 24-46% of the
dose is excreted in the urine
within 24 hours.

Thiotepa Metabolised in liver to triethylene SPC no information. Lack of information available.


phosphoramide (TEPA) Only traces Wyeth no information. Consider dose reduction, but no
of unchanged thiotepa and (TEPA) formal recommendations.
are excreted in the urine, together
with a large proportion of
metabolites (60% within 72 hours).

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 13 of 13
Drug Pharmacokinetics Available Information Recommendation

Topotecan Undergoes reversible, pH- SPC there is no experience of the use of topotecan in patients with CrCl < 20 CrCl (ml/min) Dose
dependent hydrolysis of the active ml/min and topotecan is contra-indicated in this group of patients. Plasma
lactone moiety to the inactive clearance in patients with CrCl 41-60ml/min decreased to ~67%. In moderate >60 100%
hydroxyacid (carboxylate) form. A renal impairment (CrCl 20-39 ml/min), plasma clearance was reduced to ~34%. 41-60 75%
relatively small amount of Merck Dose-limiting toxicities, mainly neutropenia and thrombocytopenia 20-39 50%
topotecan is metabolised by hepatic are seen in patients with impaired renal function. In patients with moderate <20 CI
microsomal enzymes to an active renal impairment, a starting dose of 0.75mg/m2 is recommended. Further
metabolite, N-demethyltopotecan. reductions are recommended in heavily pretreated patients.
The clinical significance of this Kintzel et al2 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl of
metabolite is not known. 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, use 0.7 fraction of
Excretion via biliary and renal dose.
route.11 20-60% is excreted in the Haemodialysis - Topotecan is effectively cleared by HD. Plasma clearance
urine as topotecan or the open ring may be increased fourfold whilst on HD12.
form.

Trastuzumab Distributes to normal cells, tumour SPC Dedicated studies in patients with renal or hepatic impairment have not Probably no dose reduction
cells and serum where HER2 been carried out. However, in a population pharmacokinetic analysis, renal necessary.
antigens are found.11 t1/2 = 28.5 impairment was not shown to affect trastuzumab disposition.
days. Roche no further information
Remains in body for 24 weeks
Doesn t require hepatic or renal
metabolism for elimination.

Treosulphan Treosulfan is a pro-drug of a SPC no information. Lack of information available.


bifunctional alkylating agent. High Medac no information. Clinical decision.
and relatively constant
bioavailability. The mean urinary
excretion of the parent compound is
~15% over 24hrs.

UFT Maximum absorption levels SPC Use with caution in patients with renal or hepatic impairment. There is Lack of information available.
(Tegafur-uracil) reached within 1-2hrs. Conversion no experience with the UFT/calcium folinate combination in patients with renal Probably no dose reduction necessary
of tegafur to 5-FU occurs via impairment. Physicians shuld exercise caution. Monitor for toxicity.
microsomal (CYP2A6) and BMS the effect of renal impairment on the excretion of UFT has not been
cytosolic enzymes. The assessed. Although the primary route of elimination of UFT is not renal,
metabolism of 5-FU follows the caution should be exercised in patients with impaired renal function. Monitor
natural pathways for uracil. Less closely.
than 20% of tegafur is excreted
intact into the urine. The 3
hydroxy-metabolites are excreted in
the urine.

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 14 of 14
Drug Pharmacokinetics Available Information Recommendation

Vinblastine Vinblastine is extensively SPC no information. No dose reduction necessary


metabolised, primarily in the liver Faulding no dose reduction necessary.
to desacetylvinblastine, which is
more active than the parent
compound. 33% of the drug is
slowly excreted in the urine and
21% in the faeces within 72 hours.11

Vincristine Metabolised by cytochrome P450 SPC no information. No dose reduction necessary


(in the CYP 3A subfamily). Lilly no dose reduction necessary.
Elimination is primarily biliary - Haemodialysis (Mayne)- Not dialysable in vitro but these results cannot be
excreted into bile and faeces (67% automatically transferred to an in vivo situation
within 72 hours, 40-50% as
metabolites). 10% excreted in urine
in 24hrs.

Vindesine Metabolised by cytochrome P450 SPC no information. No dose reduction necessary


(in the CYP 3A subfamily). Lilly no dose reduction necessary.
Elimination is primarily biliary.
(13% excreted in urine in 24hrs).

Vinorelbine Widely distributed in the body, SPC 18.5% excreted unchanged in the urine. There is no rationale for Elevation of Dose
mostly in spleen, liver, kidneys, reducing the dose in patients with impaired kidney function. Creatinine
lungs, thymus; moderately in heart, Pierre-Fabre Clearance is mainly hepatic but following dose modifications
muscles; minimally in fat, brain, should be applied (see next column) N= upper normal value. 2.5 x N No dose
bone marrow. High levels found in Haemodialysis - reduction from 25 mg/m² to 12.5 mg/m² IV for one dose on modification
both normal and malignant lung day 1 weekly (given after hemodialysis) was reported in one patient.11 2.6 x N Postpone dosing
tissues, with slow diffusion out of and reassess 1
tumour tissue.11Metabolism appears week later
to be hepatic. t½ is greater than If after a two week delay the
40hrs. Excretion is mainly by the creatinine is still elevated by
biliary route (18.5% appears in the 2.6 x N, discontinue treatment
urine)

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 15 of 15
References:
1 Schwiez. Med. Wschr. 1980; 110: No 11
2 Kintzel PE, Dorr RT. Cancer Treat Rev 1995;21:33-64
3 Bennett WM et al. Am J Kidney Dis 1983;3:155-193
4 Vepesid prescribing information; Physician s Desk Reference 1999
5 Mansi J, da Costa F, Viner C. J Clin Oncol 1992;10:1569-1573
6 Massari C et al. Cancer Chemother Pharmacol, 2000,45;157-164
7 Yoshida H et al. Cancer Chemother Pharmacol, 1994,33;450-454
8 Bennett WM et al. Dosing Guidelines for Adults. 4th ed. American College of Physicians, 1999.
9 Cancer Chemotherapy Handbook, Dorr R, Von Hoff D. 2nd Ed. 1994 (Appleton & Lange)
10 The Cancer Chemotherapy Handbook, Fischer D, Tish Knobf M, Durivage H. 4th Ed ((Mosby)
11 BC Cancer Agency. Care and Research - http://www.bccancer.bc.ca (last checked November 2003)
12 Herrington et al Cancer Chemother Pharmacol 2001;47(1):89-93
13 Tomita et al Anti-Cancer Drugs 2001;12:485-487
14 Stemmler J et al Onkologie 2002;25(1):60-63
15 Holthius JJM et al Cancer Treat Rep 1985;69:1279-1282
16 Sauer H et al Cancer Treatment Rev 1990:17(2&3): 293-200
17 Brindley Cj et al Cancer Chemother Pharmacol 1985;15(1): 66-71
18 The Renal Drug Handbook, Bunn R & Ashley C Radcliffe Medical Press, Oxford;1999:61
19 Wagner, T et al Arzneim Forsch/Drug Res, 1980;30: 1588-1592
20 Bending, MR, Finch, RE. BMJ, 1978;1: 820-821
21 Milstead,RAV,Jarman,M, BMJ,1978;1: 1145-1146
22 Wang LH et al Clin. Pharmacol. Ther, 1981;29: 365-372
23 Boros,L et al Cancer Chemother Pharmacol 1992; 31 (1): 57-60
24 Takimoto CH et al Journal of Clinical Oncology Jul 15 2003: 2664-2672
24 Tricot G et al Clin Cancer Res 1996 Jun;2(6):947-52
25 Lam MSH et al. JOPP, 2003:9;45-85

Compiled by: Susanna Daniels, March 2001


Checked by: Max Summerhayes, April 2001
Revised by: Sumantha Gabriel Sept 2003
Checked by: Susanna Daniels Nov 2003
Review Date: Nov 2005

UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 2 - updated Nov 2003) Page 16 of 16
This document was created with Win2PDF available at http://www.daneprairie.com.
The unregistered version of Win2PDF is for evaluation or non-commercial use only.