PHARMACOKINETICS AND METABOLISM OF METHOTREXATE: An Example for the Use of Clinical Pharmacology in Pediatric Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
Joseph D. Borsi, MD, PhD, Erling Sagen, Civ Ing, lnge Romslo, MD, PhD, and Peter J. Mw, MD, PhD 0 Department of Pediatrics and Clinical Chemistry, University of Trondheim, Norway
KEY WVRLN: Methotremit, pharmacokinctics, acute l p p h o b h t i c leukemia.
INTRODUCTION Methotrexate (MTX) is one of the most commonly used cytostatics, both in children and adults with malignant diseases. M T X has several unique features that are responsible for its popularity as a research subject: 1. It is active in a very wide scale of different malignant diseases.
2. It has the largest dose-range of application (3-88,000 mg/m'). 3. Many different routes of administration (i.v., ism., P.o., i. thecal, i. ventricular). 4. It is the only cytostatic agent that has an antidote (folinic acid) in clinical use. 5. The determination of M T X concentrations in serum is a clinical routine and measuring its level in other biological fluids (CSF, urine) is also rather easily available. These properties enabled the investigators to develop a great number of studies. However, the different conditions used in the studies have led to a great deal of contradictions. In spite of the numerous publications, the number of unclear facts is surprisingly high, and no agreement has been reached even in simple questions (e.g., optimal dosage, optimal duration of drug exposure, dosage and duration of the rescue administration, etc). Table 1 summarizes the results of a Medlars I1 search in CLINPROTR file, generated by the NLM's National Interactive Retrieval Service on key-
Pcdiatriic Hematology and Oncology, 7t13-33, 1990 Copyraght @ 1990 by Hemisphere Publishitg Corporation
13
14
I. D. BORSl ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
TABLE 1. Application of MTX in Children: Clinical Protocols Registered in CLINPROT File
Indication
Number of protocols
ALL ANLL BMT NHML Osteosarcoma Brain tumors Histiocytosis Retinoblastoma
96 31 27 26 9 5 2 1
Starting time of FA rescue 3-48 hours (after the beginning of MTX)
Dose of MTX p.0.: 7.5-300 mg/sq.m. i.m.: 2.5-40 mg/sq.m. i.v.: 2.5-33600 mg/sq.m. i.th.: 6.25-15 mg/sq.m. Duration of MTX administration i.v.:l-5 min-48 h p.0.: 1 day-5 days i.m.:l day-7 days Starting dose of FA rescue 3-200 mg/sq.m.
words M T X and children. The table illustrates the heterogeneity of the use of MTWfolinic acid rescue treatment in pediatric patients. Questions related to the clinical and cellular pharmacology of M T X lead to the basic problems of clinical oncology, tumor biology, biochemistry pharmacology, and genetics. However, they highlight the fact that MTX-related subjects may serve as a model in clinical and experimental cancer research. Although chemotherapeutic protocols containing methotrexate still include many features based on empiricism rather than pharmacokinetic findings, it is also true that the practical application of the results of clinical pharmacologic studies has been the most extensive and advanced for the case of methotrexate, compared with other cytostatics.
CLINICAL PHARMACOKINETICS OF METHOTREXATE The absorption of M T X after oral administration has been reported to be between 47% and 83% of the dose.'" The absolute mean bioavailability of the drug was found to be 33% (range 13%-76%) in a study from the St. Jude Children's Research H ~ s p i t a lAt . ~ dosages higher than 40 mg/m2 the bioavailability of the drug was significantly lower (17.5%; range 12.7%-22.3%) in the same study. Food is affecting the absorption of M T X (e.g., milky meal)4 and decreases the absorption of the drug. Remarkable interindividual variations are expressed in the rate and the extent of the absorption of MTX. It has been suggested that patients could be divided into fast and slow absorbers, This appears to be based on M T X serum levels 1 hour after adrninistrati~n.~ clinically important as slow absorbers seem to have a higher relapse rate of
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
PHARMACOKINETICSAND METABOLISM OF METHOTREXATE
15
acute lymphoblastic leukemia.6 However, this observation requires confirmation in further studies. The mean absolute bioavailability of M T X after i.m. administration is 76% (range 54%-112 %)3, significantly higher than after p.0. administration of the drug. However, the clinical utility of the intramuscular route of administration remains to be defined. In a recent UKALL report7 i.m. M T X did not prove to be superior to p.0.-administered M T X for maintenance therapy of leukemic children. This study group has also demonstrated that intramuscular methotrexate does not reduce the variability observed with oral administration .' The intravenously administered MTX is distributed rapidly over a volume of 18%' and then over a volume of 76% of body weight." After i.v. bolus administration of M T X half-lives of 2-8 minutes, 0.9-2 hours, 5.3-1 1 hours were found for the alpha-, beta-, and gamma-phases, respectively.""* The initial phase is explained by distribution into the tissues, the second phase by excretion and metabolism, and the third phase represents gradual release of MTX from the cells. In humans, 41 %-51% of M T X is bound to plasma proteins, primarily to albumin.I3 Protein binding of M T X becomes saturated when serum M T X M, resulting in an increased amount of free drug. 14 levels exceed 5 X We have recently demonstrated the dose-dependent pharmacokinetics of MTX" in a dose range of 0.5-33.6 g/m2/24hours. A significant correlation was confirmed between the dose and steady-state concentrations of the drug; however, the increase of the dose was accompanied by a disproportionate increase of the steady-state levels. The higher the dose, the shorter half-life, the lower volume of steady-state distribution, and the slower systemic clearance were found. We described the age dependency of M T X pharmacokinetics: 1-4-years-old patients had significantly lower steady-state levels in the serum, faster systemic clearance, and higher volume of distribution. The same set of pharmacokinetic data (obtained during and after 406 M T X infusions to 58 children) was analyzed in the context of the clinical I5a outcome of the disease. We have verified Evans' observationsI6 and our previous findings in another material,I7that the systemic clearance of the drug is significantly different in relapsed patients and those in remission (CCR). Moreover, the prognostic significance of this parameter remains valid in the dose range of 0.5-8.0 g/m'. We have also observed, that in the majority of the relapsed patients, a more than two-fold increase of the systemic clearance of MTX occurred in the consecutive treatments (Fig. 1). Theoretically, many reasons could be responsible for these findings; however, the exact explanation is still missing. The question is whether relapse is a consequence of inadequate drug exposure in these patients, or fasdincreasing systemic clearance is a
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
16
1. D. BORSl ET AL.
clinical sign of resistance to MTX. Modifications of the Norwegian Pilot Study for the treatment of Acute Lymphoblastic Leukemia (ALL) are under consideration to answer this question. Following the administration of high doses of MTX, distribution of M T X into pleural fluid or ascites may have a substantial and clinically very important effect on MTX elimination”; such a “third space” becomes a source of prolonged release of MTX. The pharmacokinetics of MTX in the serum is the main determinant of the development of systemic toxicity of the drug.’9s20 In general, the severity of toxicity is more dependent on the duration of the drug exposure than on the elevation of the concentration above the threshold.“ Table 2 summarizes M T X levels at different doses and at different times, which has been associated with an increased risk of systemic toxicity of the drug. It is clear from the Table 2 that various concentrations of M T X have been reported at various time points after the end or after the beginning of the M T X infusions predictive for increased risk of toxicity. However, patients at high risk for M T X toxicity could be identified earlier based on the calculation of pharmacokinetic parameters,’such as systemic clearance at the end of the M T X infusion and half-life of the drug at different intervals after the end of the infusion. Evans was the first to describe that a half-life longer than 3.5 hours in the first 24 hours of the postinfusion period identifies patients with delayed drug elimination of MTX.” Our studies and experience in Trondheim also confirmed that the evaluation of systemic clearance of M T X and the calculation of half-life provides an early and safe basis for the recognition
FIGURE 1. Prognostic role of change in CLs of MTX during consecutive treatments.
PHARMACOKINETICSAND METABOLISM OF METHOTREXATE
17
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
TABLE 2. "Critical" Concentrations of M T X Dose g/m2
Time after start of infusion (h)
Concentration MoVL
1-15/20h 1.5-7.514h 1.5-6/4h 1.5-6/4h 814 h 8/4h 8/4h 1.5-7.5/6h 5-18.75/6h 6-8.5/4-6h 6-8.514-6h 6-8.5/4-6h 1.5-4.5124h 1124 h 212 h 1214 h 1214 h 1214 h
68 28 28 52 28 52 76 54 30 30 54 78 48 42 46 28 48 72
5 5 1 5 1 1 1 9 5 8 8 4.2
x 10-~ x 10-6 x 10-~ x 10-~
x x 10-6 x 10-~ x 10-~ x 10-6 X X
x
9 x 10-~
5 x 10-~ 8 X lo-' 5 x 10-6 1 x 10-6 2 x 10-~
Table is adapted after C. F. Stewart" and W. R. C r o ~ n . ~ ~
of patients at high risk for delayed elimination of MTX. Therefore, we have developed a PC program (PharmCalcR)for the calculation of the pharmacokinetic parameters of MTX.'' Table 3 shows the value of different pharmacokinetic parameters associated with an elevated risk for toxicity as used by PharmCalcR program, version 1.1, for the Norwegian Pilot Study (dose: 8g/ m2/24 h, loading dose 800 mg/m2 during 1 hour)." TABLE 3. Pharmacokinetic Parameten of MTX Associated with Increased Risk of Toxicity ~
Parameter Cb y 1 (d/min/m2) AUDC mgldmin Vd L/m2 Half-life Half-life Half-life
Period after the start of the INF
Value
24 h
244
24 h
3.3 h >8.5 h
AUDC: area under the data curve; CL,,: of MTX; Vd: volume of distribution.
>12 h
systemic clearance
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
18
J. D. BORSl ET AL.
Our current routine is that CL,,, and half-life values are always calculated with PharmCalcR when M T X concentration is measured in the course of the treatment and the physician responsible for the therapy receives kinetic data together with the concentration values. Other kinetic parameters (Vd , AUDC, absolute amount of drug in the body) describing the actual therapy are calculated parallel with the treatment only if the patient is considered to be at high risk; otherwise, these parameters are calculated only after the treatment for documentation and further analysis. In addition to the fact that this method has been found to be sensitive to predict risk for toxicity, it is also useful to detect other problems related to the treatment (measurement error, hydration problem, etc). As the MTX-related mortality has been reported about 6% in one study on a large materialz5and the drug related morbidity was 10%-15% in two other efforts have to be taken to decrease these figures. The application of PharmCalcR program could be a part of these efforts.
Pharmacokineticsof MTX in the CNS
MTX is slightly soluble in water (1.6mg/ml at 25 "C)and highly ionized at physiological pH.'* M T X has a limited lipid solubility, and this property limits its ability to cross into the cerebrospinal fluid (CSF). As a consequence, M T X is routinely administered directly into the CSF via intralumbar or intraventricular route. Different schedules have been developed for the intrathecal administration of the drug. It is applied separately or combined with intermediate- or highdose M T X infusion to booster the drug levels achieved in the CSF. The conventional dose of 12 mg/m2 i.th. M T X has been in use for most of the cases until recently. However, already 11 years ago, Bleyer recognized" that i.th. doses of M T X based on the body surface area result in a higher concentration in the CSF of older patients, whereas lower levels in that of the younger ones. The reason for this finding is that the growth of the CNS does not change parallel with the BSA; the volume of the CSF reaches adult levels by 3-4 years of age, whereas BSA increases until adolescence. Bleyer has developed recommendations for the dose of i.th. M T X based on the age of the patients. The pharmacokinetically derived i. th. dose regimen based on these recommendations has resulted in a marked reduction of CNS relapses in patients with ALL.30More and more protocols now follow Bleyer's recommendations for the age-related basis of i.th. M T X dose prescriptions. It has been pointed out recently that the disappearance of M T X from the CSF is highly variable after intraventricular administration, with a half-life in Therefore, the authors in their proposal for the range of 3.9 to 20
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
PHARMACOKINETICS AND METABOLISM OF METHOTREXATE
19
rational dosing, suggest the individual adjustment of the M T X dosage according to the actual level of the drug in the CSF. It is of clinical importance that after intrathecal instillation into the lumbar CSF, the distribution of M T X into the ventricular CSF is highly variable and unpredictable; ventricular concentrations of M T X are less than 10% of that in the lumbar CSE3*O n the other hand, after systemic administration, M T X enters into the CNS with no difference between ventricular and lumbar CSF.33The equal distribution of M T X in the different CNS compartments after systemic administration of high doses was one important factor motivating the new therapeutic approach in the treatment of childhood ALL, developed by Wang and M o ~ . " ' ~ ~ When administered intravenously, the distribution of M T X into the CSF (CSF/serum distribution ratio: 191-576)depends on the duration of the infusion, dose, and also on the concomitant serum concentrations (Fig. 2).'5*36We have shown in our previous work37that at the termination of 24 hours lasting infusions of 500 mg/m2 MTX, in about one third of the patients the concentration of M T X in the CSF remains below M y which has been considered as the therapeutic level of the Later it was demonstrated3' that this level is still not achieved in the CSF in 22% of the infusions when the dose of M T X was increased to 1.0 g/m2. However, MTX concentration of M/L
A
'// .*.
n 3102 p
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
Joseph D. Borsi, MD, PhD, Erling Sagen, Civ Ing, lnge Romslo, MD, PhD, and Peter J. Mw, MD, PhD 0 Department of Pediatrics and Clinical Chemistry, University of Trondheim, Norway
KEY WVRLN: Methotremit, pharmacokinctics, acute l p p h o b h t i c leukemia.
INTRODUCTION Methotrexate (MTX) is one of the most commonly used cytostatics, both in children and adults with malignant diseases. M T X has several unique features that are responsible for its popularity as a research subject: 1. It is active in a very wide scale of different malignant diseases.
2. It has the largest dose-range of application (3-88,000 mg/m'). 3. Many different routes of administration (i.v., ism., P.o., i. thecal, i. ventricular). 4. It is the only cytostatic agent that has an antidote (folinic acid) in clinical use. 5. The determination of M T X concentrations in serum is a clinical routine and measuring its level in other biological fluids (CSF, urine) is also rather easily available. These properties enabled the investigators to develop a great number of studies. However, the different conditions used in the studies have led to a great deal of contradictions. In spite of the numerous publications, the number of unclear facts is surprisingly high, and no agreement has been reached even in simple questions (e.g., optimal dosage, optimal duration of drug exposure, dosage and duration of the rescue administration, etc). Table 1 summarizes the results of a Medlars I1 search in CLINPROTR file, generated by the NLM's National Interactive Retrieval Service on key-
Pcdiatriic Hematology and Oncology, 7t13-33, 1990 Copyraght @ 1990 by Hemisphere Publishitg Corporation
13
14
I. D. BORSl ET AL.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
TABLE 1. Application of MTX in Children: Clinical Protocols Registered in CLINPROT File
Indication
Number of protocols
ALL ANLL BMT NHML Osteosarcoma Brain tumors Histiocytosis Retinoblastoma
96 31 27 26 9 5 2 1
Starting time of FA rescue 3-48 hours (after the beginning of MTX)
Dose of MTX p.0.: 7.5-300 mg/sq.m. i.m.: 2.5-40 mg/sq.m. i.v.: 2.5-33600 mg/sq.m. i.th.: 6.25-15 mg/sq.m. Duration of MTX administration i.v.:l-5 min-48 h p.0.: 1 day-5 days i.m.:l day-7 days Starting dose of FA rescue 3-200 mg/sq.m.
words M T X and children. The table illustrates the heterogeneity of the use of MTWfolinic acid rescue treatment in pediatric patients. Questions related to the clinical and cellular pharmacology of M T X lead to the basic problems of clinical oncology, tumor biology, biochemistry pharmacology, and genetics. However, they highlight the fact that MTX-related subjects may serve as a model in clinical and experimental cancer research. Although chemotherapeutic protocols containing methotrexate still include many features based on empiricism rather than pharmacokinetic findings, it is also true that the practical application of the results of clinical pharmacologic studies has been the most extensive and advanced for the case of methotrexate, compared with other cytostatics.
CLINICAL PHARMACOKINETICS OF METHOTREXATE The absorption of M T X after oral administration has been reported to be between 47% and 83% of the dose.'" The absolute mean bioavailability of the drug was found to be 33% (range 13%-76%) in a study from the St. Jude Children's Research H ~ s p i t a lAt . ~ dosages higher than 40 mg/m2 the bioavailability of the drug was significantly lower (17.5%; range 12.7%-22.3%) in the same study. Food is affecting the absorption of M T X (e.g., milky meal)4 and decreases the absorption of the drug. Remarkable interindividual variations are expressed in the rate and the extent of the absorption of MTX. It has been suggested that patients could be divided into fast and slow absorbers, This appears to be based on M T X serum levels 1 hour after adrninistrati~n.~ clinically important as slow absorbers seem to have a higher relapse rate of
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
PHARMACOKINETICSAND METABOLISM OF METHOTREXATE
15
acute lymphoblastic leukemia.6 However, this observation requires confirmation in further studies. The mean absolute bioavailability of M T X after i.m. administration is 76% (range 54%-112 %)3, significantly higher than after p.0. administration of the drug. However, the clinical utility of the intramuscular route of administration remains to be defined. In a recent UKALL report7 i.m. M T X did not prove to be superior to p.0.-administered M T X for maintenance therapy of leukemic children. This study group has also demonstrated that intramuscular methotrexate does not reduce the variability observed with oral administration .' The intravenously administered MTX is distributed rapidly over a volume of 18%' and then over a volume of 76% of body weight." After i.v. bolus administration of M T X half-lives of 2-8 minutes, 0.9-2 hours, 5.3-1 1 hours were found for the alpha-, beta-, and gamma-phases, respectively.""* The initial phase is explained by distribution into the tissues, the second phase by excretion and metabolism, and the third phase represents gradual release of MTX from the cells. In humans, 41 %-51% of M T X is bound to plasma proteins, primarily to albumin.I3 Protein binding of M T X becomes saturated when serum M T X M, resulting in an increased amount of free drug. 14 levels exceed 5 X We have recently demonstrated the dose-dependent pharmacokinetics of MTX" in a dose range of 0.5-33.6 g/m2/24hours. A significant correlation was confirmed between the dose and steady-state concentrations of the drug; however, the increase of the dose was accompanied by a disproportionate increase of the steady-state levels. The higher the dose, the shorter half-life, the lower volume of steady-state distribution, and the slower systemic clearance were found. We described the age dependency of M T X pharmacokinetics: 1-4-years-old patients had significantly lower steady-state levels in the serum, faster systemic clearance, and higher volume of distribution. The same set of pharmacokinetic data (obtained during and after 406 M T X infusions to 58 children) was analyzed in the context of the clinical I5a outcome of the disease. We have verified Evans' observationsI6 and our previous findings in another material,I7that the systemic clearance of the drug is significantly different in relapsed patients and those in remission (CCR). Moreover, the prognostic significance of this parameter remains valid in the dose range of 0.5-8.0 g/m'. We have also observed, that in the majority of the relapsed patients, a more than two-fold increase of the systemic clearance of MTX occurred in the consecutive treatments (Fig. 1). Theoretically, many reasons could be responsible for these findings; however, the exact explanation is still missing. The question is whether relapse is a consequence of inadequate drug exposure in these patients, or fasdincreasing systemic clearance is a
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
16
1. D. BORSl ET AL.
clinical sign of resistance to MTX. Modifications of the Norwegian Pilot Study for the treatment of Acute Lymphoblastic Leukemia (ALL) are under consideration to answer this question. Following the administration of high doses of MTX, distribution of M T X into pleural fluid or ascites may have a substantial and clinically very important effect on MTX elimination”; such a “third space” becomes a source of prolonged release of MTX. The pharmacokinetics of MTX in the serum is the main determinant of the development of systemic toxicity of the drug.’9s20 In general, the severity of toxicity is more dependent on the duration of the drug exposure than on the elevation of the concentration above the threshold.“ Table 2 summarizes M T X levels at different doses and at different times, which has been associated with an increased risk of systemic toxicity of the drug. It is clear from the Table 2 that various concentrations of M T X have been reported at various time points after the end or after the beginning of the M T X infusions predictive for increased risk of toxicity. However, patients at high risk for M T X toxicity could be identified earlier based on the calculation of pharmacokinetic parameters,’such as systemic clearance at the end of the M T X infusion and half-life of the drug at different intervals after the end of the infusion. Evans was the first to describe that a half-life longer than 3.5 hours in the first 24 hours of the postinfusion period identifies patients with delayed drug elimination of MTX.” Our studies and experience in Trondheim also confirmed that the evaluation of systemic clearance of M T X and the calculation of half-life provides an early and safe basis for the recognition
FIGURE 1. Prognostic role of change in CLs of MTX during consecutive treatments.
PHARMACOKINETICSAND METABOLISM OF METHOTREXATE
17
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
TABLE 2. "Critical" Concentrations of M T X Dose g/m2
Time after start of infusion (h)
Concentration MoVL
1-15/20h 1.5-7.514h 1.5-6/4h 1.5-6/4h 814 h 8/4h 8/4h 1.5-7.5/6h 5-18.75/6h 6-8.5/4-6h 6-8.514-6h 6-8.5/4-6h 1.5-4.5124h 1124 h 212 h 1214 h 1214 h 1214 h
68 28 28 52 28 52 76 54 30 30 54 78 48 42 46 28 48 72
5 5 1 5 1 1 1 9 5 8 8 4.2
x 10-~ x 10-6 x 10-~ x 10-~
x x 10-6 x 10-~ x 10-~ x 10-6 X X
x
9 x 10-~
5 x 10-~ 8 X lo-' 5 x 10-6 1 x 10-6 2 x 10-~
Table is adapted after C. F. Stewart" and W. R. C r o ~ n . ~ ~
of patients at high risk for delayed elimination of MTX. Therefore, we have developed a PC program (PharmCalcR)for the calculation of the pharmacokinetic parameters of MTX.'' Table 3 shows the value of different pharmacokinetic parameters associated with an elevated risk for toxicity as used by PharmCalcR program, version 1.1, for the Norwegian Pilot Study (dose: 8g/ m2/24 h, loading dose 800 mg/m2 during 1 hour)." TABLE 3. Pharmacokinetic Parameten of MTX Associated with Increased Risk of Toxicity ~
Parameter Cb y 1 (d/min/m2) AUDC mgldmin Vd L/m2 Half-life Half-life Half-life
Period after the start of the INF
Value
24 h
244
24 h
3.3 h >8.5 h
AUDC: area under the data curve; CL,,: of MTX; Vd: volume of distribution.
>12 h
systemic clearance
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
18
J. D. BORSl ET AL.
Our current routine is that CL,,, and half-life values are always calculated with PharmCalcR when M T X concentration is measured in the course of the treatment and the physician responsible for the therapy receives kinetic data together with the concentration values. Other kinetic parameters (Vd , AUDC, absolute amount of drug in the body) describing the actual therapy are calculated parallel with the treatment only if the patient is considered to be at high risk; otherwise, these parameters are calculated only after the treatment for documentation and further analysis. In addition to the fact that this method has been found to be sensitive to predict risk for toxicity, it is also useful to detect other problems related to the treatment (measurement error, hydration problem, etc). As the MTX-related mortality has been reported about 6% in one study on a large materialz5and the drug related morbidity was 10%-15% in two other efforts have to be taken to decrease these figures. The application of PharmCalcR program could be a part of these efforts.
Pharmacokineticsof MTX in the CNS
MTX is slightly soluble in water (1.6mg/ml at 25 "C)and highly ionized at physiological pH.'* M T X has a limited lipid solubility, and this property limits its ability to cross into the cerebrospinal fluid (CSF). As a consequence, M T X is routinely administered directly into the CSF via intralumbar or intraventricular route. Different schedules have been developed for the intrathecal administration of the drug. It is applied separately or combined with intermediate- or highdose M T X infusion to booster the drug levels achieved in the CSF. The conventional dose of 12 mg/m2 i.th. M T X has been in use for most of the cases until recently. However, already 11 years ago, Bleyer recognized" that i.th. doses of M T X based on the body surface area result in a higher concentration in the CSF of older patients, whereas lower levels in that of the younger ones. The reason for this finding is that the growth of the CNS does not change parallel with the BSA; the volume of the CSF reaches adult levels by 3-4 years of age, whereas BSA increases until adolescence. Bleyer has developed recommendations for the dose of i.th. M T X based on the age of the patients. The pharmacokinetically derived i. th. dose regimen based on these recommendations has resulted in a marked reduction of CNS relapses in patients with ALL.30More and more protocols now follow Bleyer's recommendations for the age-related basis of i.th. M T X dose prescriptions. It has been pointed out recently that the disappearance of M T X from the CSF is highly variable after intraventricular administration, with a half-life in Therefore, the authors in their proposal for the range of 3.9 to 20
Pediatr Hematol Oncol Downloaded from informahealthcare.com by UB Giessen on 12/14/14 For personal use only.
PHARMACOKINETICS AND METABOLISM OF METHOTREXATE
19
rational dosing, suggest the individual adjustment of the M T X dosage according to the actual level of the drug in the CSF. It is of clinical importance that after intrathecal instillation into the lumbar CSF, the distribution of M T X into the ventricular CSF is highly variable and unpredictable; ventricular concentrations of M T X are less than 10% of that in the lumbar CSE3*O n the other hand, after systemic administration, M T X enters into the CNS with no difference between ventricular and lumbar CSF.33The equal distribution of M T X in the different CNS compartments after systemic administration of high doses was one important factor motivating the new therapeutic approach in the treatment of childhood ALL, developed by Wang and M o ~ . " ' ~ ~ When administered intravenously, the distribution of M T X into the CSF (CSF/serum distribution ratio: 191-576)depends on the duration of the infusion, dose, and also on the concomitant serum concentrations (Fig. 2).'5*36We have shown in our previous work37that at the termination of 24 hours lasting infusions of 500 mg/m2 MTX, in about one third of the patients the concentration of M T X in the CSF remains below M y which has been considered as the therapeutic level of the Later it was demonstrated3' that this level is still not achieved in the CSF in 22% of the infusions when the dose of M T X was increased to 1.0 g/m2. However, MTX concentration of M/L
A
'// .*.
n 3102 p
