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Pharmacokinetic and pharmacodynamic optimization of intraperitoneal chemotherapy
Life Sciences, Vol. 58. No. 7. pp. 535-543. 19% Copyright 0 I996 Elsevier Science Inc. Printed in tie USA. All rights reserved 0024-32OW96 $15.00 + .OO
0024-3205(95)02200-7 ELSEVIBR
MINIREVIEW PHARMACOKINETIC AND PHARMACODYNAMIC OPTIMIZATION OF INTRAPERITONEAL CHEMOTHERAPY
Joseph P. Balthasa?
and Ho-Leung Fung
(Received in final form November
27, 1995)
Summary Intraperitoneal drug administration has been utilized to increase chemotherapeutic exposure to tumors confined to the peritoneal cavity, such as those found in ovarian, gastric, colo-rectal and mesotheliomal cancers. Extensive pre-clinical and clinical experimentation has been conducted to assess the pharmacokinetic and therapeutic benefits of this mode of therapy. Pharmacokinetic studies have shown that the harrier function of the peritoneal membrane may be utilized to product large. lilvorable concentration gradients between peritoneal pcrfusate and blood. However, most clinical studies so far have demonstrated minimal increases in drug efficacy or decreases in drug toxicities from intraperitoneal drug therapy alone. This paper reviews the application of adjunctive therapies that have been rationally conceived to optimize intraperitoneal drug therapy through the alteration of antineoplastic pharmacokinetics and pharmacodynamics.
Key Words: ovarian, cancer, mesothelioma, intraperitoneal, chemotherapy, pharmacokinetics,
pharmacody-
namics.
Ovarian cancer is often diagnosed at advanced stages and thus is typically characterized by widely disseminated peritoneal disease (1). Advanced ovarian cancer carries a very poor prognosis, with 5year survival rates ranging from 20-35% (1,2). Peritoneal seeding is an ofien fatal complication of peritoneal mesothelioma, gastric and cola-rectal cancers (3-6). The confinement of these conditions to the peritoneal cavity coupled with the failure of systemic chemotherapy to effectively eliminate peritoneal neoplasms has led to the investigation of intraperitoneal chemotherapy as a possible treatment modality for these cancers (7-9). Unfortunately, intraperitoneal chemotherapy alone has not been shown to provide dramatic therapeutic improvements in the treatment of these disorders (10-12). Recently, several strategies have been proposed to improve the efficacy of intraperitoneal chemotherapy in the treatment of localized neoplasms. Optimization of intraperitoneal drug therapy may be ? to whom correspondence should bc addressed. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 14260. Phone: 716-645-2842. FAX 716-645-3693. EMAIL: [email protected].
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achieved by altering drug input, pharmacokinetics or pharmacodynamics such that the ratio of observed beneficial drug effects to detrimental drug effects is improved. The ultimate goal of optimization strategies is to achieve pharmacologic cures without incurring intolerable drug toxicities. This paper will review strategies of altering drug pharmacokinetics or pharmacodynamics to optimize intraperitoneal drug therapy, optimization of drug input will not be specifically addressed.
{I) Pharmacokinetic
Rationale
for Intraneritoneal
Drw Theranv
In 1978, Dedrick et al. presented a pharmacokinetic rationale for intraperitoneal drug administration in the treatment of ovarian cancer (7). These investigators noted that many antineoplastic agents would be expected to be cleared much more rapidly fi-om the systemic circulation than from the peritoneal cavity. Consequently, they reasoned that intraperitoneal administration of such agents would result in the formation of a concentration gradient across the peritoneal membrane, with higher concentrations of drug in the peritoneal cavity relative to blood. It was then suggested that peritoneal tumors could be preferentially exposed to high concentrations of anti-cancer agents while systemic tissues would be exposed to much lower drug concentrations. Assuming that antineoplastic efficacy and toxicities are related to drug concentration, this approach may allow for attaining local drug effect while limiting systemic toxicities. The hypothesized pharmacokinetic advantages of intraperitoneal drug administration have been demonstrated in clinical pharmacokinetic studies conducted with a variety of antineoplastics. Speyer and coworkers have shown that intraperitoneal bolus infusions of 5-fluorouracil ($FU) could produce peak peritoneal/plasma concentration ratios approximating 400 in ovarian cancer patients (13). Gyves et al. proceeded to demonstrate that concentration ratios exceeding 2,000 could be produced by continuous infUsions of 5-FU in patients (14). Similarly, other investigators have found patient peritoneal/ plasma concentration and area ratios (generically, R) for i.p. administration of: melphalan (R: 93, [ 15]), methotrexate (R range: 23-92, [16-l 8]), cisplatin (R: 12-21, [ 19]), doxorubicin (R: approximately 400, [20]) and cytosine arabinoside (R: 300-1000, [21]). Taken collectively, these studies have illustrated that the i.p. administration of antineoplastics does, in fact, generally produce large concentration differences between peritoneal and circulatory fluids. Despite the impressive apparent pharmacokinetic advantage related to intraperitoneal drug administration, most clinical studies have failed to show dramatic therapeutic benefits from the approach (11,22-24). Two phase III studies have been conducted which compare the efficacy of i.p. and i.v. therapies in the treatment of ovarian cancer. The first of these studies, which was somewhat flawed due to poor patient accrual, found no differences in response duration or survival between the two treatment groups (10). Recently, the results of a large intergroup study of patients with Stage III ovarian cancer have been presented (12). This study, which was designed to compare the efficacy/ toxicity of i.p. cisplatin to i.v. cisplatin (both at 100 mg/m’ with co-administration of i.v. cyclophosphamide at 600 mg/m*), found that the i.p. group had a slightly longer estimated median survival time (49 v. 41 months, p = 0.03). The authors also reported that the i.v. patients demonstrated significantly more severe and more frequent occurrences of clinical hearing loss and neutropenia. In spite of these encouraging results, the full potential of i.p. therapy for the treatment of peritoneal tumors has yet to be realized. Clearly, the benefits of intraperitoneal drug administration are determined not only by the extent of exposure achieved in the peritoneal cavity, but also by the relationship of drug in the peritoneal perfusate to cytotoxicity. This pharmacodynamic relationship is defined by a variety of factors, including: cellular rates of drug penetration and elimination, rates of metabolic activation/degradation and cellular growth rates. Optimization of intraperitoneal drug therapy may be accomplished by altering
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Optimization of lntraperitoneal Chemotherapy
the relationship of peritoneal or by altering the relationship thods).
537
drug exposure to systemic drug exposure (pharmacokinetic methods) of drug concentration to tumoricidal activity (pharmacodynamic me-
(In Pharmacokinetic /Al Utilitv of Pharmacokinetic
Optimization
of IntraDeritoneal
Chemotherapy
Odimization
The ideal outcome of chemotherapy is to completely eliminate cancerous cells from the patient without producing intolerable drug toxicities. Unfortunately for most patients with peritoneal cancers, drug toxicities often limit chemotherapeutic doses to levels below that necessary to eradicate the disease. Following intraperitoneal administration, dose-limiting toxicities may be loco-regional or systemic (resultant from drug leaking out of the cavity and into the systemic circulation). Maximal delivery of drug to the tumor is expected to result in increased benefit to the patient. Maximal systemic and regional drug delivery would be expected to simultaneously produce maximum tolerated systemic and regional toxicity. The majority antineoplastics tested for efficacy following intraperitoneal administration have been shown to produce limiting systemic toxicities with a relative absence of peritoneal toxicity (drug, reference: methotrexate, [IS]; melphalan, [ 151; SFU, [ 13,141; cisplatin, [ 191; carboplatin, [25]). For these antineoplastics, pharmacokinetic optimization may allow for maximal drug delivery by increasing peritoneal drug exposure relative to systemic drug exposure. Differential equations describing the concentration of drug in systemic and peritoneal fluids may be easily written (7). Assuming a simplistic two-compartment mamillary model with linear drug clearance, these equations are:
dc, _ D$ _ cLD ’ ‘, + dt
VP
cLD ’
VP
dC,
-=
dt
CL,
‘,
att=O,
CP=
VP
* C, _
vs
CL,
5
(1)
VP
’
C,
vs
-
CL
l
c,
vs
(2)
Where C, and C, are the concentrations of drug in the peritoneum and blood, respectively. CL, and CL are the distribution and elimination clearances of drug. This simple system ignores the possible complexities imparted by peritoneal metabolism, hepatic first-pass metabolism, non-symmetric convective (or diffusive) transport and protein binding; however, the selected system does allow rapid visualization of the effects of altering CLI, and CL, the two pharmacokinetic parameters which are most important for controlling the peritoneal and systemic exposures of most small molecule chemotherapeutics (26). Following an intraperitoneal dose of drug, the relationship of peritoneal exposure to drug (AUC,) and systemic exposure to drug (AUC,) may mathematically be shown to be:
(3)
From this equation, it is apparent that increasing the systemic clearance of drug or decreasing the distributional drug clearance will result in increasing the ratio of peritoneal : systemic drug exposure (R).
538
/Bl Pharmacokinetic
Optimization of lntraperitoneal Chemotherapy
Ootimization
Vol. 58, No. 7, 1996
ADDroaches
Alteration of Systemic drug clearance It is readily apparent from equation 3 that increasing the systemic clearance of free drug relative to the diffusional clearance of the drug will result in an increase in the ratio of peritoneal to systemic drug exposure. As systemic toxicity is often directly related to systemic antineoplastic exposure (27, 28), such an approach would be expected to allow the maximization of local drug delivery through minimization of systemic toxicities. The first example of this approach involved the addition of intravenous administration of sodium thiosulfate to intraperitoneal cisplatin therapy (19,29). It was anticipated that the presence of sodium thiosulfate in the systemic circulation would lead to the rapid complexation and inactivation of cisplatin in plasma, effectively increasing the systemic clearance of free cisplatin (30). Unfortunately, the rate of thiosulfate-cisplatin complexation was found to be insufficient to dramatically reduce systemic exposure to cisplatin (30). Interestingly, however, thiosulfate-cisplatin complexation was found to proceed rapidly in urine, substantially decreasing cisplatin nephrotoxicity. Although this approach has been used to increase the amount of cisplatin which may be given i.p., systemic (rather than local) toxicities continue to limit the tolerable intraperitoneal cisplatin dose. The use of this combined approach has not proven to be more efficacious than traditional systemic chemotherapy in the treatment of ovarian cancer (10). A new approach for optimizing intraperitoneal chemotherapy through increasing the systemic clearance of free drug has been recently described (3 1). This approach utilizes the systemic administration of anti-drug antibody fragments to rapidly bind drug that diffuses out of the peritoneal cavity. Elimination of drug bound to the antibody fragments provides an additional clearance mechanism, potentially decreasing systemic exposure to free drug. Preliminary studies conducted with digoxin and antidigoxin Fab fragments in mice have demonstrated that this approach may effectively reduce systemic exposure to free drug and systemic toxicity without reducing peritoneal drug exposure. Anti-methotrexate antibodies have since been prepared and purified for further testing this concept further (32). Intravenous administration of anti-methotrexate IgG and Fab have proven useM in reducing systemic exposure to methotrexate following an intraperitoneal dose of the antineoplastic (unpublished data). Pre-clinical pharmacokinetic studies suggest that anti-drug antibodies (or fragments) may have general utility in providing pharmacokinetic optimization of intraperitoneal chemotherapy. Application of this approach may be limited by the high cost of producing anti-drug antibodies, the potential immunogenicity of antibodies obtained from animal sources and the potential for re-distributing (rather than eliminating) chemotherapeutics (3 1). Enhancement of metabolic degradation processes may also be potentially useful for increasing the systemic clearance of antineoplastics. Such enhancement would be most beneficial if the metabolic process was: (a) specific, such that endogenous substances were not effected, (b) organ selective, i.e. metabolizing drug in the systemic circulation but not in the peritoneal perfusate, and (c) benign, i.e. leading to inactive, non-toxic metabolites. One approach which may have potential is the simultaneous peritoneal administration of methotrexate and systemic administration of carboxypeptidase-G,, which is a bacterial enzyme capable of hydrolyzing folates (33). In animal studies, this enzyme has been shown to degrade methotrexate rapidly in plasma, producing non-toxic metabolites (4-deoxy-4amino-MO-methylpteroic acid and glutamate) (34). Intravenous administration of carboxypeptidaseG, may accelerate the systemic clearance of methotrexate, potentially providing a mechanism for pharmacokinetic optimization of intraperitoneal methotrexate therapy. Unfortunately, this approach is unable to be generally applied to all antineoplastics and enzyme immunogenicity may limit the effectiveness of the approach (34).
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539
To our knowledge, traditional toxicokinetic methods utilized for enhancing drug clearance (hemodialysis, hemoperfusion, forced alkaline/acid diuresis, gastro-intestinal dialysis with activated charcoal) have not been extensively studied for decreasing systemic exposure to antineoplastics. Due to the rapid clearance of most antineoplastics, these non-specific approaches are unlikely to produce the dramatic increases in systemic clearance necessary for optimization of intraperitoneal chemotherapy. Alteration of Peritoneal Clearance Equation 3 indicates that R may be increased by reducing the diffusional clearance of drug placed in the peritoneal cavity. Due to the typically passive, (kinetically) linear nature of diffusional clearance, reducing peritoneal clearance is not practically achievable for most small-molecule drugs. However, it has been demonstrated that the peritoneal clearance of drug containing liposomes may be decreased by pre-treatment with blank liposomes (35) as illustrated by the finding that the peritoneal half-life of liposomal cytosine arabinoside may be increased from 2 1 h to 165 h. This approach may prove to be a -.rery effective, safe method to optimize intraperitoneal liposomal therapy, provided that pre-treatment with blank liposomes does not adversely effect the tumor uptake rate or tumor sensitivity to liposomal drug.
(IID Pharmacodvnamic
Outimization
ADDroaches
Pharmacodynamic approaches for optimizing drug therapy attempt to alter the relationships between drug concentration and drug effects selectively. In the case of intraperitoneal chemotherapy, it would be desirable to modulate drug phannacodynamics such that cytotoxicity occurred at lower concentrations within the peritoneum and at higher concentrations in systemic tissues. Thus, pharmacodynamic optimization approaches for intraperitoneal drug therapy attempt to either increase the potency of drug in the peritoneum or decrease the potency of drug in systemic tissues. (A) Increasing
Peritoneal
Drug Potencv
Enhancement of drug penetration It is readily appreciated that high concentrations of drug in the bulk phase (i.e. peritoneal perfusate) may not produce high concentrations of drug at the biophase (i.e. tumor cell cytosol or nucleus). Polar drugs, which would be expected to have low peritoneal clearances and high systemic clearances (and thus have high R values), would also be expected to penetrate solid tumors poorly. Poor penetrability of chemotherapeutics and immunotoxins into solid tumors has been demonstrated in a variety of experimental systems (36-40). Selective enhancement of drug penetration may be attempted on the regional or cellular level. Regional enhancement of drug penetration makes use of the barrier function of the peritoneal cavity to produce loco-regional environmental conditions which facilitate drug uptake by convective or diffusive mechanisms. Peritoneal perfusion with hyperthermic solutions has been investigated as a regional approach of enhancing drug penetration. Like the pharmacokinetic approaches previously discussed, regional hyperthermia is likely best applied to antineoplastics which demonstrate dose-limiting systemic toxicities following intraperitoneal administration. Chemotherapeutics which produce dose-limiting local toxicities (doxorubicin [20], mitoxantrone [41] and mitomycin [42]) will likely benefit only from cellular targeting methods, as potentially achieved by prodrugs and drug carriers. Hyperthermia has been shown to increase the cytotoxicity and cellular uptake of several antineoplastics in vitro and in vivo. (43-46). Intraperitoneal chemotherapy has been combined with the peritoneal perfusion of hyperthermic solutions in an attempt to increase the safety and efficacy of the respective individual approaches (47). Animal studies indicate that regional hyperthermia enhances antineoplastic cytotoxicity through a combination of cellular and systemic mechanisms (48,49). Preliminary clinical studies appear to indicate that this approach may be feasibly accomplished in patients
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(4, 50,51); however, therapeutic benefits have not yet been adequately defined (52). This approach appears to have great potential for optimizing intraperitoneal chemotherapy. Theoretically, convective transport of antineoplastics may be regionally enhanced through hypotonic peritoneal chemotherapy. The benefits of such therapy would be expected to be limited to macromolecular pharmaceuticals, which are likely heavily dependent on convective mechanisms for penetration into solid tumors and tissues (53,54). Interestingly, investigations comparing macromolecule penetration from isotonic and hypertonic peritoneal dialysates have not shown dramatic decreases in IgG penetration with increases in tonicity, contrary to expectations (53, 54). The potential benifits of hypotonic chemotherapy have not been adequately studied to date.
Cellular Modulation of Cytotoxicity Several adjuvant agents have been shown to alter cellular antineoplastic sensitivity. For example, dipyridamole has been shown to interfere with cellular uptake of nucleosides, effectively enhancing the cytotoxicity of several antimetabolites (55-57). Verapamil, cyclosporine A, quinidine and anti-pglycoprotein antibodies have been shown to decrease the rate of cellular efflux of p-glycoprotein substrates in resistant cancer cell lines, thereby increasing the cytotoxicity of these agents (58-61). Intraperitoneal administration of the modulator and the chemotherapeutic may produce high R values for both agents, potentially allowing for a selective enhancement of regional cytotoxicity (62-64). Pre-clinical and clinical studies have shown that dipyridamole appeared to dramatically increase the cytotoxicity of intraperitoneal methotrexate (55, 63). In the Phase 1 study of Goel et al., the doselimiting toxicity of this approach was found to be chemical-peritonitis, while only mild-moderate hematologic toxicities were observed in responding patients (63). These results suggest that regional cytotoxicity had been preferentially increased relative to systemic cytotoxicity, as hypothesized. Unfortunately, peritoneal disease was found to progress in the majority of evaluable patients in this study. Nevertheless, further optimization of input of both agents may result in great improvements over methotrexate therapy alone. Inhibitors of p-glycoprotein may enhance the cytotoxicity of substrate chemotherapeutics in tumors and normal tissues expressing this cellular detoxification system. Combined intraperitoneal administration of p-glycoprotein inhibitors with substrate antineoplastics may allow for the restoration chemotherapeutic efficacy against mdr-1 multidrug resistant peritoneal tumors with minimal effects on systemic tissues. However, at present little evidence exists to indicate that mdr-1 multidrug resistance occurs in a substantial percentage of peritoneal tumors, suggesting that the utility of this approach may be limited to a small subset of peritoneal cancer patients. Clinical studies are needed to identify the possible role of this combined therapy. (Bl Decreasing
Svstemic Drup Potencv
In the original paper describing the pharmacokinetic rationale for intraperitoneal drug therapy in the treatment of ovarian cancer, Dedrick et al. hypothesized that the availability of competitive antagonists of chemotherapeutics may allow for selective systemic inhibition of cytotoxicity, through combined intraperitoneal administration of the antineoplastic and intravenous administration of the antagonist (7). This approach, which does not propose to alter the disposition of the chemotherapeutic, would be expected to produce results qualitatively similar to the pharmacokinetic optimization strategies described above. It is expected that systemic antagonism of cytotoxicity would allow for increasing the dose of drug which may be given by regional infusion. Again, this approach will likely provide the most benefit in application to antineoplastics with dose-limiting systemic toxicities following peritoneal administration.
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Optimization of lntraperitoneal Chemotherapy
541
The most studied application of systemic pharmacodynamic antagonism is the addition of systemic leucovorin administration to intraperitoneal methotrexate therapy (18, 65). In a small, phase 1 study of intracompartmental methotrexate therapy combined with intravenous administration of leucovorin, responses were observed in all (eight) evaluable patients (18). The dose-limiting toxicity of therapy was myelosuppresion; however, leucovorin administration enabled methotrexate infusions to be escalated from 24 to 120 hours before myelosuppresion was encountered. In spite of these encouraging results, no additional clinical studies have been published assessing this combined treatment approach.
/IV) Drup Carriers Drug carriers have the potential of drastically altering the pharmacokinetics and pharmacodynamics of antineoplastic agents. The beneficial effects conferred by drug carriers may be further enhanced through the intraperitoneal administration. Although a review of drug carriers is well beyond the scope of this paper, it is important to note that the use of drug carriers may provide unique opportunities to optimize intraperitoneal drug therapy. Interested readers are directed to several timely reviews: liposomal therapy (66,67), immunoconjugates (68), antibody-directed enzyme prodrug therapy (69, 70), bifunctional antibody therapy (7 I).
Conclusions In spite of the apparent pharmacokinetic advantage for intraperitoneal cancer chemotherapy, intraperitoneal drug administration has not resulted in dramatic therapeutic improvements in the treatment of peritoneal tumors. However, the barrier function of the peritoneal membrane may allow for selective application of adjunctive therapies, potentially optimizing intraperitoneal chemotherapy. Adjunctive therapies may be rationally designed to impart selective alterations in the pharmacokinetics and pharmacodynamics of antineoplastics, potentially providing therapeutic gains. Pre-clinical and clinical studies are needed to assess the potential benefits of the various optimization strategies.
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0024-3205(95)02200-7 ELSEVIBR
MINIREVIEW PHARMACOKINETIC AND PHARMACODYNAMIC OPTIMIZATION OF INTRAPERITONEAL CHEMOTHERAPY
Joseph P. Balthasa?
and Ho-Leung Fung
(Received in final form November
27, 1995)
Summary Intraperitoneal drug administration has been utilized to increase chemotherapeutic exposure to tumors confined to the peritoneal cavity, such as those found in ovarian, gastric, colo-rectal and mesotheliomal cancers. Extensive pre-clinical and clinical experimentation has been conducted to assess the pharmacokinetic and therapeutic benefits of this mode of therapy. Pharmacokinetic studies have shown that the harrier function of the peritoneal membrane may be utilized to product large. lilvorable concentration gradients between peritoneal pcrfusate and blood. However, most clinical studies so far have demonstrated minimal increases in drug efficacy or decreases in drug toxicities from intraperitoneal drug therapy alone. This paper reviews the application of adjunctive therapies that have been rationally conceived to optimize intraperitoneal drug therapy through the alteration of antineoplastic pharmacokinetics and pharmacodynamics.
Key Words: ovarian, cancer, mesothelioma, intraperitoneal, chemotherapy, pharmacokinetics,
pharmacody-
namics.
Ovarian cancer is often diagnosed at advanced stages and thus is typically characterized by widely disseminated peritoneal disease (1). Advanced ovarian cancer carries a very poor prognosis, with 5year survival rates ranging from 20-35% (1,2). Peritoneal seeding is an ofien fatal complication of peritoneal mesothelioma, gastric and cola-rectal cancers (3-6). The confinement of these conditions to the peritoneal cavity coupled with the failure of systemic chemotherapy to effectively eliminate peritoneal neoplasms has led to the investigation of intraperitoneal chemotherapy as a possible treatment modality for these cancers (7-9). Unfortunately, intraperitoneal chemotherapy alone has not been shown to provide dramatic therapeutic improvements in the treatment of these disorders (10-12). Recently, several strategies have been proposed to improve the efficacy of intraperitoneal chemotherapy in the treatment of localized neoplasms. Optimization of intraperitoneal drug therapy may be ? to whom correspondence should bc addressed. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York 14260. Phone: 716-645-2842. FAX 716-645-3693. EMAIL: [email protected].
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achieved by altering drug input, pharmacokinetics or pharmacodynamics such that the ratio of observed beneficial drug effects to detrimental drug effects is improved. The ultimate goal of optimization strategies is to achieve pharmacologic cures without incurring intolerable drug toxicities. This paper will review strategies of altering drug pharmacokinetics or pharmacodynamics to optimize intraperitoneal drug therapy, optimization of drug input will not be specifically addressed.
{I) Pharmacokinetic
Rationale
for Intraneritoneal
Drw Theranv
In 1978, Dedrick et al. presented a pharmacokinetic rationale for intraperitoneal drug administration in the treatment of ovarian cancer (7). These investigators noted that many antineoplastic agents would be expected to be cleared much more rapidly fi-om the systemic circulation than from the peritoneal cavity. Consequently, they reasoned that intraperitoneal administration of such agents would result in the formation of a concentration gradient across the peritoneal membrane, with higher concentrations of drug in the peritoneal cavity relative to blood. It was then suggested that peritoneal tumors could be preferentially exposed to high concentrations of anti-cancer agents while systemic tissues would be exposed to much lower drug concentrations. Assuming that antineoplastic efficacy and toxicities are related to drug concentration, this approach may allow for attaining local drug effect while limiting systemic toxicities. The hypothesized pharmacokinetic advantages of intraperitoneal drug administration have been demonstrated in clinical pharmacokinetic studies conducted with a variety of antineoplastics. Speyer and coworkers have shown that intraperitoneal bolus infusions of 5-fluorouracil ($FU) could produce peak peritoneal/plasma concentration ratios approximating 400 in ovarian cancer patients (13). Gyves et al. proceeded to demonstrate that concentration ratios exceeding 2,000 could be produced by continuous infUsions of 5-FU in patients (14). Similarly, other investigators have found patient peritoneal/ plasma concentration and area ratios (generically, R) for i.p. administration of: melphalan (R: 93, [ 15]), methotrexate (R range: 23-92, [16-l 8]), cisplatin (R: 12-21, [ 19]), doxorubicin (R: approximately 400, [20]) and cytosine arabinoside (R: 300-1000, [21]). Taken collectively, these studies have illustrated that the i.p. administration of antineoplastics does, in fact, generally produce large concentration differences between peritoneal and circulatory fluids. Despite the impressive apparent pharmacokinetic advantage related to intraperitoneal drug administration, most clinical studies have failed to show dramatic therapeutic benefits from the approach (11,22-24). Two phase III studies have been conducted which compare the efficacy of i.p. and i.v. therapies in the treatment of ovarian cancer. The first of these studies, which was somewhat flawed due to poor patient accrual, found no differences in response duration or survival between the two treatment groups (10). Recently, the results of a large intergroup study of patients with Stage III ovarian cancer have been presented (12). This study, which was designed to compare the efficacy/ toxicity of i.p. cisplatin to i.v. cisplatin (both at 100 mg/m’ with co-administration of i.v. cyclophosphamide at 600 mg/m*), found that the i.p. group had a slightly longer estimated median survival time (49 v. 41 months, p = 0.03). The authors also reported that the i.v. patients demonstrated significantly more severe and more frequent occurrences of clinical hearing loss and neutropenia. In spite of these encouraging results, the full potential of i.p. therapy for the treatment of peritoneal tumors has yet to be realized. Clearly, the benefits of intraperitoneal drug administration are determined not only by the extent of exposure achieved in the peritoneal cavity, but also by the relationship of drug in the peritoneal perfusate to cytotoxicity. This pharmacodynamic relationship is defined by a variety of factors, including: cellular rates of drug penetration and elimination, rates of metabolic activation/degradation and cellular growth rates. Optimization of intraperitoneal drug therapy may be accomplished by altering
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Optimization of lntraperitoneal Chemotherapy
the relationship of peritoneal or by altering the relationship thods).
537
drug exposure to systemic drug exposure (pharmacokinetic methods) of drug concentration to tumoricidal activity (pharmacodynamic me-
(In Pharmacokinetic /Al Utilitv of Pharmacokinetic
Optimization
of IntraDeritoneal
Chemotherapy
Odimization
The ideal outcome of chemotherapy is to completely eliminate cancerous cells from the patient without producing intolerable drug toxicities. Unfortunately for most patients with peritoneal cancers, drug toxicities often limit chemotherapeutic doses to levels below that necessary to eradicate the disease. Following intraperitoneal administration, dose-limiting toxicities may be loco-regional or systemic (resultant from drug leaking out of the cavity and into the systemic circulation). Maximal delivery of drug to the tumor is expected to result in increased benefit to the patient. Maximal systemic and regional drug delivery would be expected to simultaneously produce maximum tolerated systemic and regional toxicity. The majority antineoplastics tested for efficacy following intraperitoneal administration have been shown to produce limiting systemic toxicities with a relative absence of peritoneal toxicity (drug, reference: methotrexate, [IS]; melphalan, [ 151; SFU, [ 13,141; cisplatin, [ 191; carboplatin, [25]). For these antineoplastics, pharmacokinetic optimization may allow for maximal drug delivery by increasing peritoneal drug exposure relative to systemic drug exposure. Differential equations describing the concentration of drug in systemic and peritoneal fluids may be easily written (7). Assuming a simplistic two-compartment mamillary model with linear drug clearance, these equations are:
dc, _ D$ _ cLD ’ ‘, + dt
VP
cLD ’
VP
dC,
-=
dt
CL,
‘,
att=O,
CP=
VP
* C, _
vs
CL,
5
(1)
VP
’
C,
vs
-
CL
l
c,
vs
(2)
Where C, and C, are the concentrations of drug in the peritoneum and blood, respectively. CL, and CL are the distribution and elimination clearances of drug. This simple system ignores the possible complexities imparted by peritoneal metabolism, hepatic first-pass metabolism, non-symmetric convective (or diffusive) transport and protein binding; however, the selected system does allow rapid visualization of the effects of altering CLI, and CL, the two pharmacokinetic parameters which are most important for controlling the peritoneal and systemic exposures of most small molecule chemotherapeutics (26). Following an intraperitoneal dose of drug, the relationship of peritoneal exposure to drug (AUC,) and systemic exposure to drug (AUC,) may mathematically be shown to be:
(3)
From this equation, it is apparent that increasing the systemic clearance of drug or decreasing the distributional drug clearance will result in increasing the ratio of peritoneal : systemic drug exposure (R).
538
/Bl Pharmacokinetic
Optimization of lntraperitoneal Chemotherapy
Ootimization
Vol. 58, No. 7, 1996
ADDroaches
Alteration of Systemic drug clearance It is readily apparent from equation 3 that increasing the systemic clearance of free drug relative to the diffusional clearance of the drug will result in an increase in the ratio of peritoneal to systemic drug exposure. As systemic toxicity is often directly related to systemic antineoplastic exposure (27, 28), such an approach would be expected to allow the maximization of local drug delivery through minimization of systemic toxicities. The first example of this approach involved the addition of intravenous administration of sodium thiosulfate to intraperitoneal cisplatin therapy (19,29). It was anticipated that the presence of sodium thiosulfate in the systemic circulation would lead to the rapid complexation and inactivation of cisplatin in plasma, effectively increasing the systemic clearance of free cisplatin (30). Unfortunately, the rate of thiosulfate-cisplatin complexation was found to be insufficient to dramatically reduce systemic exposure to cisplatin (30). Interestingly, however, thiosulfate-cisplatin complexation was found to proceed rapidly in urine, substantially decreasing cisplatin nephrotoxicity. Although this approach has been used to increase the amount of cisplatin which may be given i.p., systemic (rather than local) toxicities continue to limit the tolerable intraperitoneal cisplatin dose. The use of this combined approach has not proven to be more efficacious than traditional systemic chemotherapy in the treatment of ovarian cancer (10). A new approach for optimizing intraperitoneal chemotherapy through increasing the systemic clearance of free drug has been recently described (3 1). This approach utilizes the systemic administration of anti-drug antibody fragments to rapidly bind drug that diffuses out of the peritoneal cavity. Elimination of drug bound to the antibody fragments provides an additional clearance mechanism, potentially decreasing systemic exposure to free drug. Preliminary studies conducted with digoxin and antidigoxin Fab fragments in mice have demonstrated that this approach may effectively reduce systemic exposure to free drug and systemic toxicity without reducing peritoneal drug exposure. Anti-methotrexate antibodies have since been prepared and purified for further testing this concept further (32). Intravenous administration of anti-methotrexate IgG and Fab have proven useM in reducing systemic exposure to methotrexate following an intraperitoneal dose of the antineoplastic (unpublished data). Pre-clinical pharmacokinetic studies suggest that anti-drug antibodies (or fragments) may have general utility in providing pharmacokinetic optimization of intraperitoneal chemotherapy. Application of this approach may be limited by the high cost of producing anti-drug antibodies, the potential immunogenicity of antibodies obtained from animal sources and the potential for re-distributing (rather than eliminating) chemotherapeutics (3 1). Enhancement of metabolic degradation processes may also be potentially useful for increasing the systemic clearance of antineoplastics. Such enhancement would be most beneficial if the metabolic process was: (a) specific, such that endogenous substances were not effected, (b) organ selective, i.e. metabolizing drug in the systemic circulation but not in the peritoneal perfusate, and (c) benign, i.e. leading to inactive, non-toxic metabolites. One approach which may have potential is the simultaneous peritoneal administration of methotrexate and systemic administration of carboxypeptidase-G,, which is a bacterial enzyme capable of hydrolyzing folates (33). In animal studies, this enzyme has been shown to degrade methotrexate rapidly in plasma, producing non-toxic metabolites (4-deoxy-4amino-MO-methylpteroic acid and glutamate) (34). Intravenous administration of carboxypeptidaseG, may accelerate the systemic clearance of methotrexate, potentially providing a mechanism for pharmacokinetic optimization of intraperitoneal methotrexate therapy. Unfortunately, this approach is unable to be generally applied to all antineoplastics and enzyme immunogenicity may limit the effectiveness of the approach (34).
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Optimization of Intraperitoneal Chemotherapy
539
To our knowledge, traditional toxicokinetic methods utilized for enhancing drug clearance (hemodialysis, hemoperfusion, forced alkaline/acid diuresis, gastro-intestinal dialysis with activated charcoal) have not been extensively studied for decreasing systemic exposure to antineoplastics. Due to the rapid clearance of most antineoplastics, these non-specific approaches are unlikely to produce the dramatic increases in systemic clearance necessary for optimization of intraperitoneal chemotherapy. Alteration of Peritoneal Clearance Equation 3 indicates that R may be increased by reducing the diffusional clearance of drug placed in the peritoneal cavity. Due to the typically passive, (kinetically) linear nature of diffusional clearance, reducing peritoneal clearance is not practically achievable for most small-molecule drugs. However, it has been demonstrated that the peritoneal clearance of drug containing liposomes may be decreased by pre-treatment with blank liposomes (35) as illustrated by the finding that the peritoneal half-life of liposomal cytosine arabinoside may be increased from 2 1 h to 165 h. This approach may prove to be a -.rery effective, safe method to optimize intraperitoneal liposomal therapy, provided that pre-treatment with blank liposomes does not adversely effect the tumor uptake rate or tumor sensitivity to liposomal drug.
(IID Pharmacodvnamic
Outimization
ADDroaches
Pharmacodynamic approaches for optimizing drug therapy attempt to alter the relationships between drug concentration and drug effects selectively. In the case of intraperitoneal chemotherapy, it would be desirable to modulate drug phannacodynamics such that cytotoxicity occurred at lower concentrations within the peritoneum and at higher concentrations in systemic tissues. Thus, pharmacodynamic optimization approaches for intraperitoneal drug therapy attempt to either increase the potency of drug in the peritoneum or decrease the potency of drug in systemic tissues. (A) Increasing
Peritoneal
Drug Potencv
Enhancement of drug penetration It is readily appreciated that high concentrations of drug in the bulk phase (i.e. peritoneal perfusate) may not produce high concentrations of drug at the biophase (i.e. tumor cell cytosol or nucleus). Polar drugs, which would be expected to have low peritoneal clearances and high systemic clearances (and thus have high R values), would also be expected to penetrate solid tumors poorly. Poor penetrability of chemotherapeutics and immunotoxins into solid tumors has been demonstrated in a variety of experimental systems (36-40). Selective enhancement of drug penetration may be attempted on the regional or cellular level. Regional enhancement of drug penetration makes use of the barrier function of the peritoneal cavity to produce loco-regional environmental conditions which facilitate drug uptake by convective or diffusive mechanisms. Peritoneal perfusion with hyperthermic solutions has been investigated as a regional approach of enhancing drug penetration. Like the pharmacokinetic approaches previously discussed, regional hyperthermia is likely best applied to antineoplastics which demonstrate dose-limiting systemic toxicities following intraperitoneal administration. Chemotherapeutics which produce dose-limiting local toxicities (doxorubicin [20], mitoxantrone [41] and mitomycin [42]) will likely benefit only from cellular targeting methods, as potentially achieved by prodrugs and drug carriers. Hyperthermia has been shown to increase the cytotoxicity and cellular uptake of several antineoplastics in vitro and in vivo. (43-46). Intraperitoneal chemotherapy has been combined with the peritoneal perfusion of hyperthermic solutions in an attempt to increase the safety and efficacy of the respective individual approaches (47). Animal studies indicate that regional hyperthermia enhances antineoplastic cytotoxicity through a combination of cellular and systemic mechanisms (48,49). Preliminary clinical studies appear to indicate that this approach may be feasibly accomplished in patients
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Optimization of Intraperitoneal Chemotherapy
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(4, 50,51); however, therapeutic benefits have not yet been adequately defined (52). This approach appears to have great potential for optimizing intraperitoneal chemotherapy. Theoretically, convective transport of antineoplastics may be regionally enhanced through hypotonic peritoneal chemotherapy. The benefits of such therapy would be expected to be limited to macromolecular pharmaceuticals, which are likely heavily dependent on convective mechanisms for penetration into solid tumors and tissues (53,54). Interestingly, investigations comparing macromolecule penetration from isotonic and hypertonic peritoneal dialysates have not shown dramatic decreases in IgG penetration with increases in tonicity, contrary to expectations (53, 54). The potential benifits of hypotonic chemotherapy have not been adequately studied to date.
Cellular Modulation of Cytotoxicity Several adjuvant agents have been shown to alter cellular antineoplastic sensitivity. For example, dipyridamole has been shown to interfere with cellular uptake of nucleosides, effectively enhancing the cytotoxicity of several antimetabolites (55-57). Verapamil, cyclosporine A, quinidine and anti-pglycoprotein antibodies have been shown to decrease the rate of cellular efflux of p-glycoprotein substrates in resistant cancer cell lines, thereby increasing the cytotoxicity of these agents (58-61). Intraperitoneal administration of the modulator and the chemotherapeutic may produce high R values for both agents, potentially allowing for a selective enhancement of regional cytotoxicity (62-64). Pre-clinical and clinical studies have shown that dipyridamole appeared to dramatically increase the cytotoxicity of intraperitoneal methotrexate (55, 63). In the Phase 1 study of Goel et al., the doselimiting toxicity of this approach was found to be chemical-peritonitis, while only mild-moderate hematologic toxicities were observed in responding patients (63). These results suggest that regional cytotoxicity had been preferentially increased relative to systemic cytotoxicity, as hypothesized. Unfortunately, peritoneal disease was found to progress in the majority of evaluable patients in this study. Nevertheless, further optimization of input of both agents may result in great improvements over methotrexate therapy alone. Inhibitors of p-glycoprotein may enhance the cytotoxicity of substrate chemotherapeutics in tumors and normal tissues expressing this cellular detoxification system. Combined intraperitoneal administration of p-glycoprotein inhibitors with substrate antineoplastics may allow for the restoration chemotherapeutic efficacy against mdr-1 multidrug resistant peritoneal tumors with minimal effects on systemic tissues. However, at present little evidence exists to indicate that mdr-1 multidrug resistance occurs in a substantial percentage of peritoneal tumors, suggesting that the utility of this approach may be limited to a small subset of peritoneal cancer patients. Clinical studies are needed to identify the possible role of this combined therapy. (Bl Decreasing
Svstemic Drup Potencv
In the original paper describing the pharmacokinetic rationale for intraperitoneal drug therapy in the treatment of ovarian cancer, Dedrick et al. hypothesized that the availability of competitive antagonists of chemotherapeutics may allow for selective systemic inhibition of cytotoxicity, through combined intraperitoneal administration of the antineoplastic and intravenous administration of the antagonist (7). This approach, which does not propose to alter the disposition of the chemotherapeutic, would be expected to produce results qualitatively similar to the pharmacokinetic optimization strategies described above. It is expected that systemic antagonism of cytotoxicity would allow for increasing the dose of drug which may be given by regional infusion. Again, this approach will likely provide the most benefit in application to antineoplastics with dose-limiting systemic toxicities following peritoneal administration.
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Optimization of lntraperitoneal Chemotherapy
541
The most studied application of systemic pharmacodynamic antagonism is the addition of systemic leucovorin administration to intraperitoneal methotrexate therapy (18, 65). In a small, phase 1 study of intracompartmental methotrexate therapy combined with intravenous administration of leucovorin, responses were observed in all (eight) evaluable patients (18). The dose-limiting toxicity of therapy was myelosuppresion; however, leucovorin administration enabled methotrexate infusions to be escalated from 24 to 120 hours before myelosuppresion was encountered. In spite of these encouraging results, no additional clinical studies have been published assessing this combined treatment approach.
/IV) Drup Carriers Drug carriers have the potential of drastically altering the pharmacokinetics and pharmacodynamics of antineoplastic agents. The beneficial effects conferred by drug carriers may be further enhanced through the intraperitoneal administration. Although a review of drug carriers is well beyond the scope of this paper, it is important to note that the use of drug carriers may provide unique opportunities to optimize intraperitoneal drug therapy. Interested readers are directed to several timely reviews: liposomal therapy (66,67), immunoconjugates (68), antibody-directed enzyme prodrug therapy (69, 70), bifunctional antibody therapy (7 I).
Conclusions In spite of the apparent pharmacokinetic advantage for intraperitoneal cancer chemotherapy, intraperitoneal drug administration has not resulted in dramatic therapeutic improvements in the treatment of peritoneal tumors. However, the barrier function of the peritoneal membrane may allow for selective application of adjunctive therapies, potentially optimizing intraperitoneal chemotherapy. Adjunctive therapies may be rationally designed to impart selective alterations in the pharmacokinetics and pharmacodynamics of antineoplastics, potentially providing therapeutic gains. Pre-clinical and clinical studies are needed to assess the potential benefits of the various optimization strategies.
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