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The Oncologist, Vol. 7, No. 6, 516–530, December 2002
© 2002 AlphaMed Press

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

C.M.F. Kruijtzera, J.H. Beijnenb,c, J.H.M. Schellensa,b,c,d

a Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; b Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; c Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands; d Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence: J.H.M. Schellens, M.D., Ph.D., The Netherlands Cancer Institute/Department of Medical Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: 31-0-20-5122569; Fax: 31-0-20-5122572; e-mail: jhm{at}nki.nl


   ABSTRACT
Top
 Abstract
Introduction
 Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 
The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs.

Key Words. Cytochrome P450 • Drug transporters • Oral chemotherapy • Pharmacokinetics


   INTRODUCTION
Top
 Abstract
 Introduction
Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 
In general, the oral administration of drugs is convenient and practical. An increasing number of oral formulations of anticancer drugs have been developed in the past few years. The availability of an oral anticancer drug analogue is important when treatment must be applied chronically to be optimally effective. This concerns, for example, the 5-fluorouracil (5-FU) prodrugs (e.g., capecitabine) and drugs that interfere with signal transduction pathways or with the angiogenesis process [1]. In addition, oral drugs can be administered on an outpatient basis or at home, increasing convenience and patient quality of life, and possibly decreasing the costs by reducing hospital admissions [2]. Unfortunately, the majority of anticancer drugs has a low and variable oral bioavailability [1]. Typical examples are the widely used drugs docetaxel and paclitaxel, which have an oral bioavailibity of less than 10% [3,4]. However, several other anticancer agents with higher bioavailability demonstrate higher variability. Examples include the topoisomerase I inhibitors, the vinca alkaloids, ifosfamide, and mitoxantrone [1,5,6]. In view of the narrow therapeutic window, the variable bioavailability may result in unanticipated toxicity or decreased efficacy when therapeutic plasma levels are not achieved. Hellriegel et al. also demonstrated in a study that the plasma levels after oral administration are generally more variable than after i.v. administration [7]. Adequate oral bioavailability is also important when the period of drug exposure is a major determinant of anticancer therapy [8]. There are a number of important mechanisms that can explain the variable and/or low oral bioavailability, such as high affinity for drug transporters in the gastrointestinal tract, which limits absorption, and high extraction of the drug by extensive metabolism in the intestine and/or liver (first-pass effect) [1,4,9]. Other important factors include structural instability and limited solubility of the drug in the gastrointestinal fluids, drug-drug and drug-food interactions, motility disorders or obstructive disorders, and existence of nausea and vomiting. In this review, we discuss the role of the main involved drug transporters and metabolic enzymes in the oral bioavailability of affected substrate drugs. In addition, we describe novel methods to improve oral drug treatment by temporary inhibition of these two systems.


   PHARMACOLOGICALLY IMPORTANT DRUG TRANSPORTERS
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 
P-Glycoprotein
P-glycoprotein (P-gp, mdr1, ABCB1) (see also http://nutrigene.4t.com/abcb.htm) is a member of the ATP-binding cassette (ABC) superfamily of drug transporters first discovered by Juliano and Ling in 1976 [10]. This 170 kDa glycoprotein consists of two similar halves, each containing six putative transmembrane segments and an intracellular ATP binding site [11–13]. The protein was initially discovered through its ability to confer multidrug resistance (MDR) [10]. Acquired or intrinsic resistance of malignant cells to anticancer agents has been called MDR and results in decreased intracellular concentrations of these drugs [14]. The MDR phenotype is characterized by overexpression of P-gp, and the protein is encoded by the MDR1 gene in humans [15,16]. Mammalian P-gps are encoded by small gene families, containing two members in humans (MDR1 and MDR3) and three members in mice (mdr1a, mdr1b, and mdr2). Only the MDR1, mdr1a, and mdr1b gene products can confer MDR. Thus, in mice, two P-gps, encoded by mdr1a and mdr1b, perform the same function as the single human protein MDR1 [17–21]. P-gp is not only expressed in resistant cancer cells, but also in normal tissues with an excretory function such as the biliary canalicular membrane of hepatocytes, the luminal membrane of endothelial cells in the blood-brain barrier and blood-testis barrier, the apical membrane of the syncytial trophoblasts of the placenta, the epithelial apical membrane of the intestine, and the renal proximal tubules. By that, P-gp may possess an important barrier function in preventing tissues against xenotoxins (Fig. 1Go) [9,22–24]. In order to understand the human MDR1 P-gp functions, knockout mice lacking mdr1a and mdr1b P-gp were generated and intensively studied. Results revealed that P-gp, highly expressed in the epithelial layer of the gastrointestinal tract, limits the uptake of affected substrate drugs from the intestine into the systemic circulation [19,25,26]. In addition, in mice, the P-gp encoded by mdr1a is the major drug efflux protein in the blood-brain barrier. Absence or inhibition of this protein in mice may result in increased drug levels in tissues, especially the brain, and can result in increased toxicity [19]. Assessment of high levels of P-gp in clinical tumor samples indicate that this protein may be relevant for acquired MDR in a range of tumor types [27], and this has led to the development of modulators of this protein.



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  		Figure 1. Selected transport mechanisms in the intestinal epithelium. Localization of ABC drug transporters. P-gp, MRP2, MRP4, and BCRP localize to the apical membranes of the epithelial cells. MRP1, 3, and 5 localize to the basolateral membranes of epithelial cells.

 
A wide range of drugs with varying physicochemical characteristics and pharmacological activity, such as verapamil, quinidine, and cyclosporin A (CsA) and the new active blockers GF120918 (elacridar), LY335979 (zosuquidar), and R101933, were tested in clinical studies to modulate drug resistance [28–33]. The calcium channel blocker verapamil was the first agent found to inhibit the P-gp efflux pump in vitro. Tsuruo et al. demonstrated a decreased efflux of vincristine in P388/vincristine-resistant cell lines when verapamil was coadministered [28]. In 1984, Rogan et al. started the first clinical trial with verapamil and doxorubicin in patients with ovarian cancer [34]. Disappointingly, the majority of investigations with these drugs demonstrated that most P-gp modulators decrease the systemic clearance of anticancer drugs, thus potentially increasing the side effects associated with anticancer therapy. Mechanisms by which P-gp modulators can influence the pharmacokinetics of the anticancer agent are competition for cytochrome P450 (CYP)-mediated intestinal or liver metabolism, inhibition of P-gp-mediated biliary excretion, intestinal transport, and inhibition of renal elimination [35,36]. Only a few prospective randomized studies combining an anticancer agent with or without a modulator have been performed. These studies revealed that dose reductions of the anticancer drug, when combined with a modulator, were necessary to prevent severe drug-related toxicity. In addition, these studies did not show any survival benefit for the combination of an anticancer drug with a modulator [37–39]. A new generation of efficacious inhibitors of P-gp has become available more recently such as GF120918, LY335979, valspodar (PSC833), biricodar (VX 710), and R101933 [31–33,40,41]. Except for GF120918 and LY335979, which are suggested to be more specific inhibitors of drug transport, these drugs probably act by inhibiting P-gp as well as CYP3A, an isoenzyme of the CYP system. The overlap in substrate selectivity for P-gp and CYP3A, combined with their tissue localization, suggests that these two proteins cooperate and constitute an absorption barrier against toxic xenobiotics [42–44]. Cummins et al. have confirmed this and showed that P-gp can affect intestinal drug metabolism (especially the isoenzyme CYP3A4) by controlling the access of a drug to the intracellular metabolizing enzyme system (Fig. 2Go) [45]. The proposed interplay between these proteins in the intestine and, consequently, the combined activity of CYP3A and P-gp, may be major determinants of limited and/or variable oral bioavailability of shared substrate drugs.



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  		Figure 2. Interplay between P-gp and CYP450.

 
MDR-Associated Proteins
In 1992, Cole et al. discovered a second type of drug efflux pump, the multidrug resistance protein (MRP) [46]. Like P-gp, MRPs are members of the ABC drug transporters and have the capacity to mediate transmembrane transport of many (conjugated) drugs and other compounds. The information about the MRP family is expanding rapidly and nine members have been identified (see also http://www.humanabc.org) [47,48]. MRP1 (MRP, GSX, ABCC1), which is present in all human tissues, is localized at the basolateral side of the plasma membrane and pumps substrate drugs into the body [49,50]. Studies in mrp1 knockout mice have confirmed this localization (Fig. 1Go) [48,51–53]. MRP1 functions mainly as a cotransporter of organic anions. It can transport hydrophobic drugs or other compounds that are complexed or conjugated to the anionic tripeptide glutathione (GSH), to glucuronic acid, or to sulphate [48,49,54]. Some drugs are conjugated to GSH by glutathione S-transferase and then transported by MRP. Other drugs are cotransported with GSH. Thus, MRP1 can be considered a glutathione-S-conjugate pump. Efficient export of several (anticancer) drugs by MRP1 is dependent on a normal cellular supply of GSH [55]. In addition, MRP1 is able to transport methotrexate (MTX), an anorganic anion, and the unanswered question remains whether MRPs (e.g., MRP1) play a role in MTX resistance [56,57]. Furthermore, MRP1 also has a protective role in preventing accumulation of toxic compounds and drugs in epithelial tissue covering the choroid plexus/cerebrospinal fluid (CSF) compartment, oral epithelium, Sertoli cells in testicular tubules, urinary collecting duct cells, and white blood cells [52,58]. For example, in mrp1 knockout mice, the CSF concentrations of intravenously administered etoposide were substantially increased compared with wild-type mice [59]. Other substrate drugs for MRP1 are mitoxantrone, anthracyclines, camptothecins, epipodophyllotoxines, and the vinca alkaloids. MRP2 (cMOAT, ABCC2) is located mainly at the apical membrane in the liver canaliculi, renal proximal tubules, and gut epithelium (Fig. 1Go) [47]. However, MRP2 is also present at the luminal side of the endothelial cells in the brain capillaries [48,60].

Like MRP1, MRP2 is primarily an organic anion transporter, thus it is likely that weakly basic drugs are cotransported with GSH by MRP2. In addition, it is a major transporter of bilirubin glucuronides and other organic anions from liver to bile. This physiological function can explain why patients with the defective gene in Dubin-Johnson syndrome, which results in absence of MRP2 in the bile canaliculi, develop conjugated hyperbilirubinemia [61,62]. There is large overlap between the spectrum of compounds transported by MRP2 and MRP1. Examples of cytotoxic drugs that are substrates for MRP2 include mitoxantrone, anthracyclines, camptothecins, etoposide, vincristine, and vinblastine [48]. It has also been established that MRP2 transports the HIV protease inhibitor, saquinavir [63]. SN-38, the active metabolite of irinotecan, is also transported by MRP2 in vivo [64]. Both MRP1 and MRP2 are highly expressed in several tumor types (e.g., renal clear cell carcinoma and colorectal cancer), and these proteins may play a role in clinical drug resistance. Until now, however, in vitro studies using cell lines selected for MDR have failed to demonstrate an association between expression of MRP1 or MRP2 and MDR thus far, and, therefore, the exact contribution of these MRPs to treatment failure is still unknown [50,60,65]. Attempts to find inhibitors of MRP have mainly focused on MRP1 and MRP2. Most compounds that efficiently block MDR1 P-gp have only low affinity for MRP1 and MRP2. Thus, there are currently no effective and specific MRP inhibitors available [48,50]. MRP1 can confer resistance to arsenite [66], a compound that can induce remissions in promyelocytic leukemia, and MRP2 to cisplatin by transporting these compounds in complexes with GSH [67].

The major physiological functions of MRP3-9 are still unknown, and extensive description of these proteins is beyond the scope of this review. MRP3 and MRP5, like MRP1, are also localized at the basolateral membrane of epithelial cells, and MRP4 at the apical side (Fig. 1Go) [68–71]. Overexpression of some of these proteins may also play a role in drug resistance to MTX or nucleoside analogues [68–71]. Future studies should address the potential clinical significance of expression of these proteins. Modulation of these proteins may play a role in conferring MDR as well as in the pharmacokinetics of substrate drugs. Whether long-term inhibition of MRPs in humans can be tolerated is still unknown.

Breast Cancer-Resistance Protein
Breast cancer-resistance protein (BCRP) was first described by Doyle et al. in the human MCF-7 MDR breast cancer cell line that was selected for resistance to doxorubicin [72]. BCRP acts as an ATP-dependent xenobiotic efflux transporter. BCRP cDNA sequences were also cloned by Miyake et al. and Allikmets et al., who called the gene MXR (mitoxantrone resistance) and ABCP (placental ABC protein) [73,74]. BCRP primarily localizes at the apical side of the plasma membrane where it can actively extrude these drug substrates (Fig. 1Go) [75,76]. The tissue distribution of human BCRP shows similarities with that of P-gp, suggesting an overlap in function. BCRP is highly expressed in the small intestine, but it was also found in the bile ducts of the liver, and in the colon, placenta, veins, and capillaries [76]. The murine bcrp1 was moderately expressed in the placenta but highly expressed in the kidney, where humans appear to have low expression [72,74,75]. BCRP was not detected in human erythrocytes, leukocytes, or platelets. However, Zhou et al. demonstrated high expression of BCRP/bcrp1 in primitive hematopoetic cells, especially in the so-called side population, but the exact biological role of this finding is unknown [77]. Studies have shown that BCRP is expressed in ovarian cancer cell lines, which were made resistant to topotecan. This resulted in a major increase in the efflux rate of topotecan and related topoisomerase I inhibitory drugs [78]. Additionally, cell lines selected for resistance to mitoxantrone, doxorubicin, and SN-38 all overexpressed BCRP, which indicates that these drugs are also substrates for BCRP and bcrp1 [79].

GF120918 is a known potent inhibitor of P-gp without an effect on MRP1 [80], and was also recently identified to be an efficient inhibitor of BCRP, both in human and murine systems [79,81,82]. A recent study showed that GF120918 is a potent reversal agent of BCRP-mediated resistance to camptothecins [82]. By chance, it was discovered that CI1033 (a HER tyrosine kinase inhibitor) also inhibits BCRP [83]. Expression of BCRP in capillary endothelial cells suggests that BCRP has a protective role for these cells. Thus, BCRP has a pharmacological and possibly toxicological protective role that is comparable with P-gp, which may be its main physiological function.


   CYP SYSTEM
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
 CYP System
Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 
For anticancer drugs, CYP is the main oxidative drug-metabolizing enzyme system. CYP is highly expressed in the liver and intestines, but the exact contribution of each of these in the biotransformation of substrate drugs is unknown. In humans, CYP consists of approximately 12 families and 17 subfamilies [84], but there is only a small number of these enzyme families that is responsible for the majority of drug oxidation [85]. It is recognized that intestinal extraction by this enzyme system plays an important role in limiting oral bioavailability of drugs [86]. Humans have four identified functional CYP3A genes and proteins: CYP3A3, 4, 5, and 7. Enzymes of the CYP3A family are the predominant drug metabolizing enzymes and account for approximately 30% of hepatic CYP and more than 70% of intestinal CYP expression [42,85,87,88]. CYP3A4, the principal isoenzyme, is located at the apex of mature enterocytes, adjacent to the microvillus border [89] and is responsible for significant first-pass metabolism of orally administered drugs (e.g., CsA) [90]. We know from the literature that there is a large interindividual variability in expression of CYP3A in the liver, as can be measured with the erythromycin breath test [85]. Hepatic and intestinal CYP3A4 appear to be the same enzyme, but there is no correlation between levels of intestinal CYP3A4 protein and hepatic CYP3A activity [88,91].

A second important CYP3A isoenzyme, CYP3A5, is expressed in only 10%-30% of adult livers, where it accounts for 14%-32% of the hepatic CYP3A [42,92]. It is also expressed in the small intestinal tissue but at lower levels than CYP3A4 [88,91,92]. In addition, this isoenzyme is expressed in extrahepatic tissues including blood, kidney, and lung. Another isoenzyme of the CYP3A family is CYP3A7, which has been detected only in the liver at very low levels, but not in the small intestine [93,94]. Finally, CYP3A3, which was initially identified as the glucocorticoid-inducible CYP in human liver, is almost identical to CYP3A4 in nucleotide and amino acid sequence but differs from CYP3A4 by 11 amino acids [95].


   MODULATION OF BIOAVAILABILITY
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 
Studies attempting to increase the bioavailability of orally administered drugs have been performed in mice and humans with several anticancer drugs (e.g., the taxanes and topoisomerase I inhibitors) and also with noncytotoxic drugs such as protease inhibitors. Protease inhibitors are important drugs in the treatment of HIV-1 infection.


   IMPROVED ORAL TAXANE BIOAVAILABILITY
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
Improved Oral Topotecan...
 Conclusions and Further...
 References
 
The taxanes, paclitaxel and docetaxel, have proven anticancer activity in several tumor types (e.g., breast, ovarian, head and neck cancer, and non-small cell lung cancer [NSCLC]). Currently, the drugs are administered intravenously at different dosages and schedules [96].

Paclitaxel
When paclitaxel is administered orally, the bioavailability is very low (<10%). This is caused by the high affinity of paclitaxel for P-gp, which is present in the gastrointestinal tract [4,22,97,98]. In addition, presystemic elimination in the intestinal wall and liver by the CYP isoenzymes 3A4 and 2C8 may also play a role in the low oral bioavailability of paclitaxel [99–101]. Recent studies with wild-type mice and mdr1a P-gp knockout mice have shown unambiguously that P-gp limits the absorption of paclitaxel. In a proof-of-concept study in knockout mice compared with wild-type mice, the investigators demonstrated a sixfold and a twofold increase of the area under the plasma concentration-time curve (AUC) of paclitaxel after oral and i.v. administration, respectively [4]. The fraction of unchanged paclitaxel recovered from the feces of wild-type mice after oral administration was 87% of the dose compared with 3% in mdr1a P-gp knockout mice. Despite the complete absorption from the gastrointestinal tract, the bioavailability did not increase to 100%, probably due to first-pass intestinal/hepatic extraction [4,102].

Based on this observation, several new studies have been initiated with P-gp inhibitors in combination with paclitaxel in order to enhance the oral bioavailability. Studies in mice revealed that coadministration of SDZ PSC833, a cyclosporin D analogue and potent P-gp inhibitor, with paclitaxel resulted in a 10-fold increase in systemic exposure [103]. A similar study was performed with CsA and paclitaxel that has shown comparable effects [104]. The oral bioavailability in wild-type mice increased from 9% to 67% when CsA was coadministered. It was also noted that the plasma levels of paclitaxel obtained in wild-type mice cotreated with CsA were even higher than those obtained in knockout mice that were treated with oral paclitaxel without CsA. This can be explained by increased uptake by inhibition of P-gp in the gastrointestinal tract and decreased elimination by inhibition of CYP3A [104–107]. However, blockade of other yet unidentified drug transporters or drug eliminating pathways cannot be ruled out.

Because the use of CsA for long-term oral dosing may be complicated by potential immunosuppressive effects, an alternative, nonimmunosuppressive P-gp blocker, GF120918, was explored to enhance the oral bioavailability of paclitaxel. GF120918 was primarily developed to reverse P-gp-mediated MDR in tumors [31]. In a recently published study, Bardelmeijer et al. demonstrated that GF120918 significantly increased the oral bioavailability of paclitaxel [108]. The oral bioavailability of paclitaxel in wild-type mice increased from 8.5% to 40% and the pharmacokinetics of paclitaxel in wild-type mice receiving GF120918 were similar to that found in mdr1a/b knockout mice. Thus, GF120918 effectively blocks P-gp in the intestines and most likely does not interfere with other pathways involved in paclitaxel uptake or elimination. Of note, it was recently demonstrated that GF120918 is also an effective inhibitor of the ABC drug transporter BCRP (ABCG2) [81,82].

Docetaxel
Docetaxel is also a substrate of P-gp, first shown in 1994 by Wils et al. [109,110]. Because of the encouraging results obtained with paclitaxel in combination with P-gp inhibitors, studies in mice were also performed with docetaxel. These studies confirmed that P-gp also plays an important role in the low bioavailability of docetaxel. The AUC of oral docetaxel increased ninefold by coadministration with CsA [111]. In addition, coadministration of ritonavir, a very effective inhibitor of CYP3A4 with minor P-gp inhibiting properties, was tested in mice. CYP3A4 is the major enzyme responsible for metabolic breakdown of docetaxel in humans [112]. Preclinical studies in which ritonavir was coadministered with docetaxel have shown an increase in the apparent bioavailability from 4% to 183%, and extensive first-pass metabolism might also largely contribute to the low bioavailability of oral docetaxel in mice [111]. Thus, inhibiting P-gp as well as CYP3A4 may be an important strategy to improve the systemic exposure to oral docetaxel.

Clinical Studies with Oral Taxanes
Based on the extensive preclinical results, several clinical proof-of-concept studies were initiated. Patients with solid tumors received one course of 60 mg/m2 oral paclitaxel as a single agent, or 60 mg/m2 oral paclitaxel in combination with 15 mg/kg CsA. Coadministration of oral CsA resulted in an eightfold increase in the systemic exposure to oral paclitaxel, and the apparent bioavailability of oral paclitaxel in this study rose from 4% without CsA to 47% with CsA (Fig. 3Go) [3]. This increase in systemic exposure was most likely caused by inhibition of P-gp in the gastrointestinal tract, but inhibition of paclitaxel metabolism also may have contributed to the effect, as was concluded from the preclinical studies [103,104]. In fact, a significant reduction in the paclitaxel metabolite 3'-p-hydroxypaclitaxel has been shown, which indicates that CYP3A4 is inhibited [113]. In order to further increase the systemic exposure of paclitaxel, a dose escalation study with oral paclitaxel in combination with CsA revealed that the maximum tolerated dose was 300 mg/m2 and the increase in AUC at the higher doses was not proportional with dose [114]. At this highest dose level, a mass balance study was performed to measure fecal excretion. At the highest dose level of 300 mg/m2, the total fecal excretion was 76%, 61% of which was the parent drug, which can be explained by incomplete absorption of orally administered paclitaxel from the gastrointestinal tract [115]. We speculated that the high amount of the cosolvent Cremophor EL in the paclitaxel i.v. formulations used for oral administration prevents complete absorption of orally applied paclitaxel. We are currently testing Cremophor EL-free solutions to further optimize oral applicability of paclitaxel. In addition, Cremophor EL, which is responsible for the nonlinear pharmacokinetics of i.v. paclitaxel and for the severe hypersensitivity reactions, was not absorbed following oral administration of paclitaxel, as plasma levels of Cremophor EL were not detected [116–118]. This may be an additional advantage of oral paclitaxel administration [113,114]. Subsequently, in order to increase the duration of systemic exposure of oral paclitaxel above a threshold level of 0.1 µM, a bidaily (b.i.d.) dose regimen of oral paclitaxel in combination with CsA was explored in patients. At the dose level of 2 x 90 mg/m2, adequately long systemic exposure of paclitaxel above the level of 0.1 µM was reached with a good safety profile [119]. Additionally, a dose-finding study of oral paclitaxel with CsA showed that P-gp inhibition by CsA was maximal at a single dose of 10 mg/kg [120].



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  		Figure 3. Effect of a single oral dose of CsA (15 mg/kg) on the systemic exposure of oral paclitaxel (60 mg/m2) in patients. Reproduced with permission [3].

 
In another phase I study, patients received 1,000 mg GF120918 1 hour prior to oral paclitaxel [121]. The increase in systemic exposure to paclitaxel was of the same magnitude as in combination with CsA. Based on the results of these phase I studies, phase II studies were initiated to investigate whether repeated oral administration of paclitaxel was feasible and active. Oral paclitaxel was given b.i.d. once a week in several tumor types: as first- and second-line treatment in NSCLC, as first-line treatment in advanced gastric cancer, and as second-line treatment in advanced breast cancer. All patients were treated with weekly oral paclitaxel b.i.d. in a dose of 90 mg/m2. CsA, in a dose of 10 mg/kg, was given 30 minutes prior to every paclitaxel dose. Table 1Go shows the overall response rates (ORRs) in patients with advanced NSCLC and advanced gastric cancer. The study in patients with advanced breast cancer is still ongoing and final results are not yet available. In the patients with advanced NSCLC, the ORR was 26% in 23 evaluable patients [122]. This is comparable with the literature, as were the median time to progression of 3.5 months and median overall survival of 6 months. These studies, in which several single agents such as vinorelbine, gemcitabine, and the taxanes were used, revealed response rates between 8%-40% and median overall survival ranged from 6-11 months [123–128].


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  		Table 1. Phase II studies with oral paclitaxel plus CsA in advanced NSCLC and advanced gastric cancer, and oral docetaxel plus CsA in advanced breast cancer
 
In advanced gastric cancer, chemotherapy is given with palliative intent. Combination chemotherapy with agents such as 5-FU/doxorubicin combined with mitomycin or methotrexate, or the epirubicin/cisplatin/5-FU regimen are schedules that are frequently used and have shown response rates between 20%-50% [129–132]. Paclitaxel has also shown antitumor activity in patients with advanced gastric cancer (ORR: 5%-23%) in first- and in second-line treatment [133–135]. The ORR in our study was 32% in 24 evaluable patients (Kruijtzer et al. submitted for publication). The toxicity profile of this b.i.d. weekly schedule is well manageable. The most prevalent toxicity in the group of patients with NSCLC was grade 3/4 neutropenia, which was observed in 54% of patients. This is comparable with the standard every-3-week i.v. paclitaxel schedule [127,128]. Febrile neutropenia in our study occurred in only 12% of patients.

The prevalence of neurotoxicity was lower compared with the every-3-week schedule, which may be explained by the lower peak plasma concentrations of paclitaxel in our study. This was also observed in patients who received the 24-hour infusion versus the 3-hour infusion of paclitaxel [136], although it can be questioned whether paclitaxel plasma levels after i.v. administration (thus in the presence of Cremophor EL) can be compared with those after oral paclitaxel (thus without Cremophor EL).

In the patients with advanced gastric cancer, the most frequently recorded toxicities were nausea, vomiting, and diarrhea. Although the majority of patients already presented these symptoms before start of treatment, they worsened during treatment. Eight percent of patients discontinued oral medication because of intolerable toxicity. The hematological toxicity in these chemonaïve patients was very mild, which may be explained by sufficient bone marrow reserve. Pharmacokinetic analyses in both studies showed therapeutic levels of paclitaxel above 0.1 µM of 10.7 ± 5.6 hours and 9.1 ± 3.7 hours, respectively. The interpatient variabilities expressed as %CV in systemic AUC were 45% and 25%, respectively, which is slightly higher than after i.v. therapy [116,136]. The intrapatient variabilities in both studies were low (%CV: 15% and 12%) and indicated limited variation over time in absorption and elimination processes per patient.

For docetaxel, a similar clinical proof-of-concept study was carried out in patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m2 with or without a single oral dose of CsA 15 mg/kg. Pharmacokinetic results showed that coadministration of oral CsA resulted in a 7.3-fold increase of the systemic exposure of docetaxel. The apparent bioavailability of oral docetaxel increased from 8% without CsA to 90% with CsA [137]. This increase in systemic exposure can be explained by inhibition of CYP3A4, as well as by P-gp inhibition in the gastrointestinal tract by CsA, but the magnitude of both mechanisms cannot be determined exactly. The effect of CsA on the bioavailability of docetaxel was less pronounced in mice [111] compared with humans [137], but the reasons for this modest effect in mice are not clear. A phase II study in advanced breast cancer with weekly oral docetaxel plus CsA was also performed at our institute. This schedule was given weekly for 6 weeks followed by a 2-week rest. A weekly oral dose of 100 mg docetaxel was given, leading to an AUC equivalent to a weekly i.v. dose of 40 mg/m2, which was reasonably well tolerated [138]. CsA was given 30 minutes prior to the intake of oral docetaxel in a dose of 15 mg/kg. The i.v. formulation of docetaxel was used as a drinking solution. In 25 patients evaluable for response, an ORR of 52% was noted (Table 1Go). The most frequently recorded toxicities were neutropenia, diarrhea, nail toxicity, and fatigue. However, hematological toxicity seems to be less severe than after i.v. administration [139]. The response rate in this study is in the upper range of results described in the literature [138–141].

The inter- and intrapatient variabilities in the AUC of docetaxel after oral administration were in the same range as observed after i.v. administration of docetaxel (29%-53%) [142,143].

The weekly or b.i.d. administration of an oral dose of CsA, in combination with oral docetaxel or paclitaxel, could result in renal toxicity or infections due to immunosuppression [144]. However, in all oral taxane studies, no toxicity related to CsA was observed. This can most likely be attributed to the weekly administration of the drug, while in the transplantation setting CsA is ingested on a chronic daily basis. The absence of immune-related toxicity has been confirmed by immunological measurements. The results revealed no significant effects on T-cell counts (Kruijtzer et al. submitted for publication). Coadministration of a P-gp inhibitor may also cause increased central neurotoxicity because P-gp has a protective function in the brain [19,145]. However, in all studies, we did not observe central neurotoxicity, confirming the safety of our approach.

Intensive weekly oral schedules with taxanes are feasible and show clinically meaningful activity in advanced breast, gastric, and NSCLC. The oral schedule is convenient and has a favorable hematological toxicity profile, and the nonhematological toxicity is acceptable. Future plans are to investigate the activity of oral taxanes in combination with other P-gp blockers. Exploration of the efficacy and benefit in phase III studies in several tumor types (e.g., advanced breast cancer) is of great interest. Furthermore, we are focusing on optimizing the pharmaceutical formulation of the applied taxanes.


   IMPROVED ORAL TOPOTECAN BIOAVAILABILITY
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
Conclusions and Further...
 References
 
Topotecan is a semisynthetic water-soluble analogue of the alkaloid camptothecin and inhibits topoisomerase I, an essential enzyme involved in DNA replication [146,147]. Previous studies reported 30%-44% bioavailability of the i.v. formulation of topotecan administered orally [5,6,148]. In a phase I study, the maximum tolerated oral dose for topotecan was 2.3 mg/m2 for the daily-times-five dosing schedule [149]. Until recently, there was no mechanistic explanation for the low bioavailability of orally administered topotecan. The drug is soluble and chemically stable under physiological conditions and there is no significant first-pass metabolism [150]. In cell lines developed by us, which overexpress the drug efflux pump BCRP (ABCG2), increased efflux of topotecan could be inhibited by coincubation of the effective BCRP (and P-gp) blocker, GF120918 [81,82].

Preclinical studies in groups of mdr1a/b knockout mice and wild-type mice, which were treated with oral topotecan in combination with one single oral dose of GF120918, have shown that the systemic exposure of oral topotecan increased almost sevenfold and almost 10-fold, respectively [75]. Administration of i.v. topotecan in combination with oral GF120918 resulted in a decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re)uptake in the small intestine [75]. These results confirm that GF120918 is also an effective inhibitor of BCRP. The affinity of topotecan for P-gp is low [151], thus the affinity of topotecan for this putative drug transporter (BCRP) in the gastrointestinal tract is the most plausible explanation for the limited absorption of orally administered topotecan when given alone. Based on the preclinical research, we hypothesized that BCRP expressed in the gastrointestinal tract significantly determines the oral bioavailability of topotecan.

Clinical Studies with Oral Topotecan
We performed a clinical study of two cohorts with eight patients each. In the first cohort, eight patients were randomized to receive 1.0 mg/m2 oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918. In the second cohort, eight other patients were randomized to receive 1.0 mg/m2 i.v. topotecan with or without 1,000 mg oral GF120918. Clinical studies with GF120918 have shown that this agent is well tolerated in doses of 1,000 mg b.i.d. over 5 consecutive days in combination with doxorubicin and as a single dose of 1,000 mg with paclitaxel [121,152]. Coadministration of oral GF120918 in combination with topotecan resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40% to 97% (Fig. 4Go). The plasma-concentration time curves of the patients treated with oral topotecan plus GF120918 showed increased peak plasma concentrations compatible with increased absorption. The results of the patients treated with i.v. topotecan with or without GF120918 revealed that GF120918 had a small but significant effect of approximately 10% on the AUC and systemic clearance of total topotecan, but no significant effect on terminal half-life or Cmax of total topotecan [153]. Presumably, the increase in systemic exposure of oral topotecan results from multiple mechanisms caused by GF120918, including increased intestinal absorption and decreased clearance [153].



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  		Figure 4. Significant increase in the AUC of total topotecan in eight patients in two cohorts: with and without GF120918. Reproduced with permission [153].

 
These encouraging results may have important clinical implications for the oral application of topotecan (and other topoisomerase I inhibitors) and drugs with low oral bioavailability due to affinity for BCRP. This concept will be tested in future clinical studies. In these studies, we will determine the minimal dose of GF120918 resulting in maximal increase in oral bioavailability of topotecan. In conclusion, coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase in the apparent bioavailability and thus systemic exposure of oral topotecan [153].

Modulation of the Pharmacokinetics of Irinotecan
Irinotecan is an important drug used in the treatment of colorectal cancer and a substrate of the CYP3A4 isoenzyme [154,155]. It is a prodrug of the active metabolite, SN-38, and is converted by the CYP3A4 enzyme into several inactive metabolites. Recently, Kehrer et al. demonstrated that concomitant administration of irinotecan with ketoconazole, an inhibitor of CYP3A4, causes alteration in the metabolism of irinotecan [156]. They showed that ketoconazole considerably increased the plasma concentrations of SN-38 as a result of inhibition of CYP3A4-mediated biotransformation. It was also previously shown that CsA, another inhibitor of CYP3A4, results in significantly reduced clearance of irinotecan in humans [157]. Consequently, these interactions can result in serious toxicity and may require dose reductions. The combination of irinotecan with an inducer of CYP3A4, for example St. John’s Wort, can result in decreased levels of the active metabolite [158]. Whether modulation of the metabolism of irinotecan with drugs that are substrate for CYP3A4 will influence treatment outcome is still unknown. Treatment with irinotecan should be monitored closely when drugs that are known to affect the biotransformation of SN-38 are coadministered.

Improvement of Protease Inhibitor Bioavailability in the Treatment of HIV-1
Since multidrug therapy demonstrated to be more effective than mono- or dual therapy for the treatment of HIV-1 infection, combinations of at least three different antiretroviral drugs (including 1-2 protease inhibitors) are currently routinely used and are generally referred to as highly active antiretroviral therapy [159]. These drugs have a peptidomimetic structure and the utility is hampered by low oral bioavailability, resulting from poor absorption and/or rapid hepatobiliary elimination [160,161]. The activity of protease inhibitors is dependent on continuously adequate plasma levels to suppress viral maturation [161]. Consequently, food restriction is frequently necessary with high doses of protease inhibitors, which may negatively influence patient compliance to the therapy [162]. The currently available protease inhibitors are approximately 90% metabolized by the CYP450 isoenzymes, primarily CYP3A4 in the liver and small intestine. This extensive first-pass metabolism of the protease inhibitors may contribute to the poor and variable bioavailability of this class of drugs [161]. Since protease inhibitors are mainly eliminated presystemically by CYP3A4, coadministration of an inhibitor of CYP3A4 results in an increased systemic exposure of one or both protease inhibitors [86,162,163]. Currently, ritonavir is extensively used as an inhibitor of CYP3A [160,164] to improve oral pharmacokinetics of saquinavir and lopinavir. The latter combination (ritonavir/lopinavir [Kaletra®]), in which the dose of ritonavir is only 100 mg, allows for a convenient dosing regimen. In vitro studies have shown that most protease inhibitors are also substrates for P-gp [165–168]. In mdr1a/b knockout mice, Huisman et al. have shown that ritonavir is a poor P-gp inhibitor even at high doses [169]. Thus, the most plausible explanation for the improved apparent bioavailability of protease inhibitors in combination with ritonavir is through CYP3A4 inhibition. Nevertherless, P-gp may play a role in the penetration of protease inhibitors in sanctuary sites for HIV replication such as the central nervous system, testes, and in the placenta [169,170]. In mdr1a/b knockout mice in which expression of P-gp is absent, concentrations of protease inhibitors in the CSF were two- to fivefold higher compared with wild-type mice, suggesting a role for P-gp [171,172].

As a consequence, modulation of P-gp may result in an increase in the CSF levels of the protease inhibitors and this may have clinical implications as well. The presence of P-gp in the placenta limits fetal exposure to several compounds, but temporary inhibiting of P-gp can enhance the levels of protease inhibitors and consequently protect the fetus against HIV infection [169]. In general, modulation of the pharmacokinetics of protease inhibitors in the combination treatment against HIV-1 can be realized by coadministration of a strong inhibitor of CYP3A4, such as ritonavir.


   CONCLUSIONS AND FURTHER PERSPECTIVES
Top
 Abstract
 Introduction
 Pharmacologically Important Drug...
 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
References
 
There are several cytotoxic drugs given orally with low and highly variable bioavailability. For a number of drugs, this is due to the activity of drug transporters and metabolic enzymes in the gastrointestinal tract and liver. Molecular mechanisms have been unraveled by studies in vitro in selected cell lines and in mdr1 P-gp knockout and wild-type mice. Proof-of-concept studies in patients revealed improved oral pharmacokinetics of affected substrate drugs. Phase II studies in patients with advanced NSCLC, gastric, and breast cancer have demonstrated good clinical activity and tolerability of oral taxanes in combination with CsA.

Future randomized studies will, hopefully, confirm that the oral route is at least equally effective as standard i.v. dosing, and better in terms of patient convenience and pharmacoeconomics for drugs with affinity for drug transporters and/or CYP when applied in combination with an effective and safe inhibitor.


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 Introduction
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 CYP System
 Modulation of Bioavailability
 Improved Oral Taxane...
 Improved Oral Topotecan...
 Conclusions and Further...
 References
 

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Received July 19, 2002; accepted for publication September 11, 2002.




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