Cyclophosphamide

Cyclophosphamide (CPA) is a well-studied compound that illustrates many of the challenges faced in PKDT for HDC preparative regimens. Based on its strong immunosuppressive effect and its relative sparing of the gastrointestinal tract, CPA has been widely used in combination with other agents in preparative regimens for HDC in autologous and allogeneic HSCT. At high doses, its toxicity profile includes cardiac necrosis, veno-occlusive disease (VOD) of the liver, and hemorrhagic cystitis.

CPA is an inactive prodrug that undergoes a complex metabolic process, which starts with hydroxylation by the cytochrome P450 system (Figure 1). Studies of the PK of CPA and 4-OH-CPA/aldophosphamide have offered differing results, with an inverse correlation between the areas under the curve (AUCs) of the parent drug and 4-OH-CPA observed by some authors,¹⁵ and a direct correlation between their AUCs noted by others.¹⁶ Inactivating reactions also play a role in CPA metabolism. Hepatic or erythrocyte aldehyde dehydrogenase isoenzymes, particularly ALDH-1, can oxidize aldophosphamide to inactive metabolites that are excreted in the urine. In addition, CPA can also be excreted unchanged in the urine or undergo P450-mediated inactivation. The AUC of CPA decreases and that of 4-OH-CPA increases from day 1 to day 2 in patients treated with high-dose CPA over 2 days, which appears related to a reduction of ALDH-1 activity during treatment.¹⁷ It has been observed that acrolein, a degradation product of 4-OH-CPA, inhibits ALDH-1.¹⁸

Figure 1.

Metabolic process of CPA.

Full figure and legend (32K)

Measurement of the parent compound CPA for PKDT has important limitations. The P450-mediated hydroxylation of CPA is subject to multiple drug–drug interactions at the microsomal level, such as those with ondansetron^19,20 or ciprofloxacin.²¹ When administered at high doses, CPA displays nonlinear elimination kinetics, in a fashion dependent both on concentration and time.^22,23 A seven-fold intersubject difference in exposure to 4-OH-CPA was observed after CPA-TBI, where CPA is given first, and thus, is not subject to drug-radiation interactions. Further, a three-fold interindividual variation exists in the erythrocyte fraction of ALDH-1, an enzyme that plays an important role in the detoxification of 4-OH-CPA.²⁴ Thus, variations in the hematocrit may also change CPA disposition.

We analyzed 427 patients treated at the University of Colorado with high-dose CPA, combined with cisplatin and BCNU.²⁵ We observed that neither the absolute value of CPA AUC on day 1, nor the pattern of AUC change (increase, decrease, or minimal/no change) between days 1 and 2, predicted the pattern of change from day 2 to 3, its AUC on day 3, or its total AUC. This nonpredictable intrapatient PK behavior of CPA calls into question the feasibility of its PKDT.

It has been argued that the target molecule for CPA monitoring should not be the parent compound, but rather, its active metabolites, 4-OH-CPA or aldophosphamide.²⁶ Study of the actual exposure to these reactive and extremely unstable intermediates has been limited in the past by analytic methodology. Real-time PKDT requires rapid sample analysis with results available the next morning prior to the subsequent CPA dose, and only recently have accurate and reproducible assays been developed for determination of CPA metabolites.^27,28,29 However, the technical complexity of these assays may hamper their broad applicability. In addition, it remains unclear whether the measurement of plasma concentrations of 4-OH-CPA, like the quantitation of the parent drug, reflects the intracellular concentrations of phosphoramide mustard, the ultimate metabolite responsible for the alkylating effect.

PD analyses attempting to correlate toxic and outcome end points with CPA PK parameters have also offered conflicting results. Inverse correlations between CPA AUC and both cardiotoxicity and tumor response have been reported.^30,31 In contrast, we did not observe any significant correlation between the total CPA AUC and the occurrence of toxic death, cardiotoxicity, relapse, or overall survival in 427 patients treated at the University of Colorado.^32,33,34

McDonald et al³⁵ recently reported a prospective PD analysis of 147 patients treated with CPA-TBI. The metabolism of CPA was highly variable, particularly for the metabolite carboxyphosphamide, whose AUC varied 16-fold. Systemic exposure to carboxyphosphamide, a nontoxic oxidation product of 4-OH-CPA/aldophosphamide by ALDH1, but not to 4-OH-CPA or to any other toxic metabolite, correlated significantly with liver toxicity, nonrelapse mortality, and survival.

While CPA has been traditionally considered a mainstay of HDC, it is becoming increasingly unclear whether it truly presents a clinical dose–response effect, particularly in patients with solid tumors. A shift from activating toward inactivating reactions has been demonstrated after single administrations of high doses of CPA, indicating saturation of bioactivating enzymes, compared to conventional doses.³⁶ In contrast, no increment of inactivating reactions was apparent when administration of high-dose CPA was split over 2 days.³⁷ In contrast to the marked dose–response effect of CPA metabolites in vitro, two large randomized trials testing dose escalation with G-CSF support of CPA, combined with adriamycin, in the adjuvant treatment of node-positive breast cancer, failed to show improvements in DFS or OS after substantial increases of up to four-fold in the dose-intensity or total dose.^38,39

The complex metabolism and PK of CPA, the inability to obtain consistent PD results, its limited dose escalation potential compared to other agents, its widespread use at lower doses prior to HSCT, increasing the probability of resistance induction, have all led to a decrease in enthusiasm for CPA in preparative regimens compared to other antineoplastic compounds with less PD variation or simpler PK determination.

Melphalan

Based on its toxic profile at conventional doses, which consists mainly of myelosuppression, and its steep dose–response curve, melphalan has long been included in HDC combinations with stem-cell support. While in its first trials high-dose melphalan was administered orally, the current use of melphalan is largely currently restricted to the intravenous (i.v.) route, which avoids the problem of its inconsistent oral absorption.⁴⁰ Melphalan does not require metabolic activation. It undergoes spontaneous hydrolysis in the plasma, with inactive monohydroxy and dihydroxy metabolites appearing within minutes of the drug administration. About 15% of the drug is excreted intact in the urine. It is highly bound to proteins, mainly albumin. Melphalan is actively transported into cells, mostly by the high-affinity L-amino-acid transport system, which also carries glutamine and leucine.

Melphalan PK remain linear when delivered at high doses, in a range from 140 to 220 mg/m².^41,42,43 Its distribution fits a two-compartment model, with an elimination half-life (t₁/2) of 45–60 min, which allows the infusion of stem cells within 8–24 h of melphalan administration. After high-dose therapy, mean peak cerebrospinal fluid concentrations may reach 10% of the corresponding plasma concentrations.⁴⁴

The dose-limiting toxicity (DLT) of high-dose melphalan is gastrointestinal mucositis. While there has been considerable concern about the use of high-dose melphalan given its potential for long-term carcinogenesis, recent data suggest that the preceding standard-dose therapy is more likely the cause of secondary leukemia or myelodysplastic syndrome after melphalan-containing HDC.⁴⁵ No clear PD associations have been established between any PK parameter and the occurrence of nonhematological side effects at high doses of this drug.

Age does not appear to have a major impact on the PK of high-dose melphalan.^46,47 The effect of renal failure in the PK and the toxicity of high-dose melphalan remains unclear. In a study using conventional doses of the drug, the incidence of severe myelosuppression increased in patients with BUN concentrations above 30 mg/dl.⁴⁸ Some authors have observed increased toxicity and perturbation of the half-life and AUC of the drug when administered at high doses to patients with renal insufficiency.^49,50 However, other groups have reported the safety of high-dose melphalan in renal failure, including some on chronic hemodialysis, either administered at 200 mg/m²,⁵¹ or at 80 mg/m² in combination with high-dose busulfan.⁵²

There is up to 10-fold interpatient variability in the PK exposure to high-dose melphalan, which makes PKTD an attractive prospect. The feasibility of PKTD of melphalan administered at standard doses after a smaller test dose has been proven feasible, with less than 15% deviation from the target AUC.^53,54 Current research is exploring PKDT of high-dose melphalan, using either the test-dose approach in single-administration schedules, or dose modifications based on the PK of the first dose, when the drug is delivered in multiple administrations. Determination of target AUCs would need previous identification of PD correlations with a toxic or an outcome end point.

Thiotepa

Owing to its apparent benefit as a single agent against breast cancer in early NSABP adjuvant therapy trials,⁵⁵ and its almost 20-fold dose increase potential for HDC with HSCT,^56,57 thiotepa became an integral component of two important HDC regimens for breast cancer: STAMP-V (CPA/thiotepa/carboplatin, administered concurrently in 96-h continuous infusions),⁵⁸ and the Dutch CTC combination (same drugs administered in nonconcurrent short infusions).⁵⁹ Thiotepa markedly inhibits the activating step from CPA to 4-OH-CPA, which may have deleterious clinical consequences when both drugs are administered concurrently.⁶⁰ Thiotepa has also been used in allogeneic HSCT preparative regimens in combination with CPA and TBI.^61,62,63 Thiotepa is rapidly metabolized by cytochrome P450, through oxidative desulfuration, to its main metabolite, tepa, which shows an alkylating activity that is comparable to that of the parent compound. About 2% of the drug is excreted unchanged in the urine.

Several authors have reported direct correlation between PK of thiotepa and tepa with mucositis or other toxicities (Table 2). A population model has been described that allows estimation of individual PK with limited sampling, using a Bayesian approach.⁶⁴ In its clinical testing in 46 patients receiving CTC, this model achieved a reduction in the variability of thiotepa exposure.⁶⁵

BCNU (Carmustine)

BCNU is currently used at standard doses in the treatment of brain tumors and melanoma. Its steep dose–response effect in vitro and predominant myelotoxicity at conventional doses provided the rationale for inclusion of BCNU in HDC regimens, for example, in combination with CPA and cisplatin for breast cancer (STAMP-I), or with etoposide, ara-C, and melphalan (BEAM) for lymphoma. BCNU undergoes plasma hydrolysis, which produces reactive intermediates necessary for cytotoxicity. Additionally, in rodents, it undergoes glutathione conjugation or microsomal denitrosation that result in deactivation. Since the parent compound is highly reactive, immediate stabilization with ethyl acetate is required after blood sampling for accurate PK measurements.

In early phase I trials of single-agent BCNU with stem-cell support, liver toxicity and encephalopathy were DLTs at 1200 mg/m².⁶⁶ In contrast, its most prominent side effect when part of the STAMP-I regimen at 600 mg/m² is steroid-responsive interstitial pneumonitis. Pretreatment with cisplatin and cyclophosphamide produces large increases in both the value and the variability of BCNU AUC.⁶⁷ PD correlations between the AUC of BCNU and pulmonary toxicity have been observed by some authors,⁶⁸ but not others⁶⁹ (Table 2).

Platinum compounds

Cisplatin and carboplatin form intrastrand and interstrand DNA crosslinks. They are both activated by hydrolysis, partly dependent on the chloride concentration, to monoaquo and diaquo species. The conversion rate is lower for carboplatin than for cisplatin, which may explain the higher dose of carboplatin necessary to cause a similar cytotoxic effect. For both platinum compounds, the fraction unbound to plasma proteins is considered pharmacologically active.

Dose escalation of cisplatin is rapidly limited by nephro and ototoxicity. Thus, the doses of cisplatin used in HDC are only moderately higher than those used in conventional treatment. In contrast, the DLT of carboplatin at conventional doses is myelosuppression, which suggested the possibility of large escalations with stem-cell support. Shea et al⁷⁰ established the MTD of carboplatin at 2000 mg/m², which represents a five-fold increment over its standard dose. DLTs were hepatotoxicity, nephrotoxicity, and ototoxicity. Linear PK were observed across the range of doses tested. Subsequently, carboplatin was combined with other agents in regimens such as STAMP-V (at 800 mg/m²),⁵⁸ or CTC (at 1600 mg/m²).⁵⁹ The combination of carboplatin and etoposide,⁷¹ with or without cyclophosphamide⁷² or ifosfamide,^73,74 has become the backbone of HDC for germ cell tumors. Carboplatin-based HDC combinations have been extensively studied for treatment of children with brain tumors.^75,76

Carboplatin constitutes the first example of successful application of PKDT in cancer medicine. In the conventional setting, dosing carboplatin according to Calvert's formula,⁷⁷ based on creatinine clearance, instead of fixed dosing based on the body surface area, results in lower incidence of severe thrombocytopenia.⁷⁸ The benefits of the application of this formula in the transplant setting are less clear. In one study, renal toxicity correlated with the AUC calculated retrospectively with this formula.⁷⁹ Some investigators have conducted dose-escalation studies of carboplatin using Calvert's formula, and have noted satisfactory degrees of correlation between the desired and the measured AUCs. Schilder et al⁸⁰ have identified a target AUC of 16 as the MTD of carboplatin when administered combined with paclitaxel in multiple stem-cell supported cycles. Others, however, have warned against the use of Calvert's formula in the transplant setting. Mazumdar et al⁸¹ noted substantial discrepancies between the target AUCs predicted with this formula and the measured AUCs of carboplatin when administered at high doses. Limited sampling methods for estimation of the carboplatin AUC have been tested successfully in the transplant setting.^{82,83,84,85,86}

Taxanes

The DLT of paclitaxel infused over 24 h is myelosuppression.⁸⁷ Linear PK were noted in a phase I study of paclitaxel with stem-cell support conducted at the University of Colorado.⁸⁸ However, nonlinear PK of high-dose paclitaxel have been reported by other authors,^89,90 which appear consistent with the nonlinearity observed at conventional doses of this drug.⁹¹ PD analyses of high-dose paclitaxel have also offered contradictory results (Table 2).

Docetaxel is a potent drug against solid tumors, most notably breast cancer. Preclinical data suggest a dose-dependent, schedule-independent antitumor activity. Neutropenia is dose limiting at its MTD of 100 mg/m². A phase I trial conducted at the University of Colorado explored its dose escalation with stem-cell support in combination with high-dose melphalan and carboplatin.⁹² The MTD of docetaxel was reached at 400 mg/m² over 2 h. PK studies showed linear PK of high-dose docetaxel, which reflects nonsaturation of its hepatic metabolism, and contrasts with most data from high-dose paclitaxel. PD correlations with polyneuropathy and stomatitis have been noted (Table 2).

Busulfan

Busulfan (Bu) is a bifunctional alkylating agent active as the parent compound and converted in the liver to inactive metabolites by a glutathione-reductase-dependent mechanism.^93,94 There are no reports of vesicant activity and it is absorbed from the gut and circulates as parent drug. The drug has limited use outside of HSCT because of marked myelotoxicity and cumulative dose-related pulmonary toxicity. Historically given as the 'BuCy2' regimen of oral Bu in a q 6 h schedule for 16 doses of 1 mg/kg each (total dose 16 mg/kg) followed by Cy 60 mg/kg once daily for two doses (total dose 120 mg/kg).^95,96 Bu has become the most widely used drug in allogeneic HSCT and has had extensive use in autologous transplantation as well.⁹⁷ Complete response rates for such Bu-based regimens exceed 50% for AML, CML, ALL, and NHL.

VOD of the liver is the most serious side effect of Bu-based preparative regimens.^98,99,100 VOD occurs with a frequency of approximately 20%, and a mortality of 6–12% in patients who receive 16 mg/kg oral Bu-based preparative regimens. Vassal,¹⁰¹ Grochow,¹⁰² and Dix¹⁰³ have demonstrated an association between AUC for busulfan plasma concentration and risk of this complication. Dix further demonstrated that VOD is seldom observed when the AUC of first dose busulfan in a 16-dose regimen is less than 1500 mol/min.¹⁰³

PKDT with the oral formulation is made difficult due to erratic GI absorption from dose to dose and between patients combined with highly variable Bu half-life. Extensive sampling, complex pharmacokinetic modeling, and significant interpretation expertise is necessary for accurate performance of PKDT with oral Bu. At least 25% of patients remain inevaluable in consecutive series^102,103 and the range in first dose AUC achieved varied three-fold. Simple Bu dose reduction can reduce the risk of VOD, but correlation of higher relapse rates with low AUC have been reported by Bollinger¹⁰⁴ in ALL and Slattery¹⁰⁵ in CML.

Slattery et al¹⁰⁶ have also shown a strong correlation of graft rejection with extremely low Bu steady-state concentration (C_ss) <200 ng/ml, equivalent to first dose AUC <300 mol/min (Both C_ss and AUC are useful ways to look at busulfan concentration, but AUC is the historical standard for PK/PD study and was used in the initial and subsequent presentations to the FDA in the busulfex approval process.). A recent report from this group suggests that it is possible to assure an average concentration over 16 doses of orally administered Bu above a minimum target to reduce relapse risk.¹⁰⁷ This requires an eight-sample strategy PK on dose 1, 5, and 9 and rapid turnaround time for dose adjustment.

The availability of i.v. Bu (Busulfex^®, Orphan Medical, Inc, Minnetonka, MN, USA) has bypassed many of the problems associated with oral administration. PK profiles from 103 patients in the initial phase II trials demonstrated virtual elimination of intrapatient variability.¹⁰⁸ In addition, intravenous use eliminates variation in time to maximum drug concentration. However, only 67% of patients were within a broad therapeutic window of 900–1350 mol/min for dose 1, so significant interpatient variability remains. In an elegant review of patients treated for CML with i.v. Bu-based regimens and allogeneic HSCT, Andersson et al¹⁰⁹ have demonstrated a shortened overall survival correlation with first dose AUC greater than 1400 mol/min or less than 900 mol/min due to toxicity and relapse, respectively.¹⁰⁹

Studies done at UAB have demonstrated that a single-compartment, first-order elimination model very well describes the PK of i.v. Bu. A limited sampling strategy that allows accurate and inexpensive AUC determination on 100% of patients has been developed and validated.^110,111 Several investigators have now begun to use rapid turnaround first dose PK of i.v. Bu routinely to assure dosing precision for clinical trials including full dose and reduced-intensity preparative regimens.^112,113,114 Recent results suggest that simple PK on a test dose can accurately predict AUC of subsequent doses in a therapeutic regimen.¹¹⁵

It is now possible to define the range of acceptable target AUC of Bu for different clinical situations based upon this work and clinical observations from the existing empiric clinical trials. In the Orphan Medical Phase 1 trial, the dose 1 median Bu AUC achieved with 0.8 mg/kg of i.v. Bu was approximately equal to the AUC achieved with a 1 mg/kg oral dose.¹¹⁶ In the larger Phase 2 trial, the median AUC for first dose i.v. Bu given as 0.8 mg/kg proved to be approximately 1200 mol/min.¹⁰⁹ Thus, full-dose i.v. Bu may be reasonably defined at about 1250 mol/min. In patients receiving PKDT at this level at our center, we continue to see typical full-dose Bu regimen-related toxicity (RRT), although with the markedly reduced interpatient variation in AUC and no VOD.

The low end of the range of first dose Bu AUC in full-dose regimens with either the i.v. or oral formulation is around 400 mol/min AUC and failure to engraft was not seen in the Phase 2 trials of i.v. Bu¹⁰⁹ or in studies with the oral preparation by Slattery¹⁰⁶ and Hobbs.¹¹⁷ Thus, Bu AUC between 400 and 1200 mol/min can reasonably be considered the safe range from the point of view of low risk for failure to engraft or high risk of fatal RRT. Whether an even lower dose of Bu could be used with the addition of other immunosuppressive agents in the preparative regimen is under active investigation.

At UAB, all Bu dosing is PK directed to a specific target AUC determined by clinical protocol according to a general algorithm (Table 4).¹¹⁵ This has created a platform for quality assurance activity and research to improve outcomes for individual patients and advancement of the field.

Table 4 - Algorithm for selection of Bu dose intensity in Bu-based preparative regimens (AUC, 16 dose regimen).

Full table

Conclusion

The goal of the use of PKDT is reduction in the variability of drug exposure, which may reduce toxicity and/or increase efficacy of the treatment. Studies performed to date and reviewed here have provided us with extensive PK knowledge and identification of PD correlations for several important drugs that comprise our high-dose armamentarium, most notably the widely used drug busulfan. Continued PK and PD, including outcome measures, research will permit successful application of this approach to greater numbers of transplant patients.

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