Pharmacokinetics and Pharmacodynamics of Lobaplatin (D-19466) in Patients with Advanced Solid Tumors, Including Patients with Impaired Renal Or Liver Function

Vol. 5, 2349–2358, September 1999 Clinical Cancer Research 2349

Pharmacokinetics and Pharmacodynamics of Lobaplatin (D-19466) in Patients with Advanced Solid Tumors, Including Patients with Impaired Renal or Liver Function

Jan Welink, Epie Boven, Jan B. Vermorken, concluded that the hematological toxicity and the pharma- Helen E. Gall, and Wim J. F. van der Vijgh1 cokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated Department of Medical Oncology, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, the well with the creatinine Cl and the thrombocyte surviving Netherlands fraction. In patients with renal function, represented by a creatinine clearance > 30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is ABSTRACT expected to lead to an acceptable extent of thrombocytope- The purpose of this study was to determine the influ- nia in a patient with a given renal function. Prospective ence of impaired renal and liver function on the pharmaco- studies with larger groups of patients are needed to prove kinetics and pharmacodynamics of lobaplatin in cancer pa- the value of this dosage formula. tients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients INTRODUCTION had normal organ function or an impaired liver or renal Lobaplatin (D-19466; 1,2-diammino-methyl-cyclobutane- function (two levels). The starting dose of lobaplatin was 50 platinum(II)-lactate) is a new anticancer agent and a represent- mg/m2 i.v. given every 3 weeks. The blood and urine of all ative of the third-generation platinum compounds. Lobaplatin patients were sampled for the determination of (ultrafilter- consists of a nearly 50%/50% mixture of two diastereoisomers: able) platinum, intact lobaplatin, creatinine, and blood cell (a) the SSS configuration (LP-D1); and (b) the RRS configura- counts. No objective responses were recorded. Five patients tion (LP-D2) (Fig. 1). The compound has shown antitumor experienced no change and received 4–10 cycles (median, 6 activity in human lung, gastric, testicular, and ovarian cancer cycles) of lobaplatin. The extent and duration of hematolog- xenografts, with incomplete cross-resistance to cisplatin in vitro ical toxicity were worse in patients with impaired renal and in vivo (1–4). Compared with cisplatin or carboplatin, function. Thrombocytopenia was most prominent; grade 4 lobaplatin significantly prolonged the survival of mice bearing toxicity was observed in 15 patients in the first two cycles of P388 leukemia and a cisplatin-resistant P388 variant (1). treatment. The concentration-time curves of ultrafilterable Phase I and II studies with lobaplatin have demonstrated platinum and intact lobaplatin revealed almost identical responses in relapsed ovarian cancer (5–7), esophageal cancer patterns. The elimination of ultrafilterable platinum [final (8), head and neck cancer, breast cancer, and small cell lung ؎ ؍ ؎ ؍ half-life (t1/2 final) 131 15 min; clearance (Cl) 125 2 cancer (9). The dose-limiting toxicity of lobaplatin is thrombo- 14 ml/min/1.73 m ] was much faster than that of total plat- cytopenia, with a nadir at approximately 2 weeks after drug ؎ ؍ ؎ ؍ inum (t1/2 final 6.8 4.3 days, Cl 34 11 ml/min/1.73 2 administration. Leukopenia is less severe than thrombocytope- m ). No pharmacokinetic differences were observed between nia, and the drug does not induce nephrotoxicity, neurotoxicity, patients with normal organ function and those with an or ototoxicity. impaired liver function within the investigated range. An Because of the potential clinical use of lobaplatin and the impaired renal function resulted in an increase of the t 1/2 final limited and conflicting pharmacokinetic results (low urinary due to a decrease of the total body Cl that resulted in a 2 platinum excretion and short t1/2 final; Refs. 6 and 10), it was higher exposure of the body to the drug. The calculated decided to reestablish the pharmacokinetics of lobaplatin after creatinine Cl was linearly correlated with the total body an i.v. bolus injection not only in patients with normal renal and ؍ clearance of ultrafilterable platinum (r 0.91), which re- liver function but also in patients with impaired renal or liver AUCؕ (1.1 Cl ؉ 16), in ؍ sulted in the dosage formula D CrU function. The pharmacokinetics and pharmacodynamics of which D represents dose, AUC represents area concentra- lobaplatin were also determined during the second and third tion-time curve, and Cl represents creatinine Cl. The CrU cycle to check for any possible cumulative effects due to repet- thrombocyte surviving fraction correlated well with the itive dosing. In addition, pharmacokinetic-pharmacodynamic ؍ AUC value of ultrafilterable platinum (r 0.72). It can be relationships were established.

2 Received 3/18/99; revised 6/7/99; accepted 6/9/99. The abbreviations used are: t1/2 final, final half-life; SF, surviving The costs of publication of this article were defrayed in part by the fraction; C-t, concentration-time; Cl, clearance; MRT, mean residence payment of page charges. This article must therefore be hereby marked time; ALAT, alanine aminotransferase; ASAT, aspartate aminotrans- advertisement in accordance with 18 U.S.C. Section 1734 solely to ferase; ␥-GT, ␥-glutamyltransferase; AUC, area under the concentration indicate this fact. curve; Hb, hemoglobin; AUC/D, normalized AUC; % D, percentage of 1 To whom requests for reprints should be addressed. the dose.

Table 1 Patient characteristics Characteristic No. No. of patients 25 Sex Male 9 Female 16 Age (yrs) Median 52 Range 30–73 WHO performance score 04 118 23 Prior therapy None 2 Chemotherapy 15 Chemotherapy and radiotherapy 7 Radiotherapy only 1 Tumor type/location Ovary 7 Colon or rectum 5 Non-small cell lung cancer 3 Cervix 2 Fig. 1 Structural formulas of the two diastereoisomers of lobaplatin Unknown primary 1 (D-19466). Breast 1 Oropharynx 1 Esophagus 1 Pancreas 1 Soft tissue sarcoma 1 PATIENTS AND METHODS Prostate 1 Bladder 1 Patients and Treatment Schedule. A total of 25 patients entered this study after they had given informed consent. Pa- tients had recurrent or metastatic disease from solid tumor types with progression after standard treatment. WHO performance status was Յ2. All patients had adequate bone marrow function, A starting dose of 50 mg/m2 lobaplatin was given as an i.v. i.e. leukocyte count Ն 4 ϫ 109/liter, neutrophil count Ն 2 ϫ bolus injection in 1 min every 3 weeks. The dose was reduced 109/liter, and platelet count Ն 150 ϫ 109/liter. The patients were (by 10 mg/m2) in case of severe hematological (grade 4 for Ͼ7 stratified according to their renal and liver function to the days) or nonhematological toxicity (grade 3 or more, except for following four groups: (a) normal renal and liver function nausea/vomiting and alopecia) or when a treatment delay of [serum creatinine Ͻ 110 ␮mol/liter (1.24 mg/dl) and/or creati- more than 2 weeks was necessary. The patients were not hy- nine Cl Ͼ 79 ml/min/1.73 m2 and bilirubin Ͻ 20 ␮mol/liter drated before or after drug administration, and there were no (1.18 mg/dl), and no elevated level of ALAT (Յ44 units/liter), restrictions on food or fluid intake. ASAT (Յ31 units/liter), or ␥GT (Յ50 units/liter) for males and Pretreatment and Follow-Up Studies. Before initiation Յ38 units/liter for females)]; (b) impaired renal function level I of therapy, all patients had a history and physical examination, (serum creatinine ϭ 110–165 ␮mol/liter (1.24–1.87 mg/dl) an assessment of WHO performance status, a chest radiograph, and/or creatinine Cl ϭ 55–79 ml/min/1.73 m2); (c) impaired appropriate radiological tests to determine measurable or evalu- renal function level II (serum creatinine ϭ 166–330 ␮mol/liter able disease, an audiogram, and routine laboratory studies that (1.88–3.73 mg/dl) and/or creatinine Cl ϭ 30–54 ml/min/1.73 included a complete blood count with a differential leukocyte m2); and (d) liver impairment due to metastases [bilirubin ϭ count, electrolytes, urea, creatinine, bilirubin, alkaline phospha- 20–50 ␮mol/liter (1.18–2.94 mg/dl) and/or at least one elevated tase, ASAT, ALAT, ␥-GT, lactate dehydrogenase, albumin, enzyme level (ALAT, ASAT, or ␥GT) up to a maximum of five total protein, glucose, coagulation tests, dipstick urinalysis, and times the upper limit of normal]. Patients with renal impairment creatinine clearance. An assessment of safety consisting of were divided into two groups to obtain enough patients within a clinical assessment, adverse events, and a complete blood count certain level of renal impairment. Each group consisted of six with differential and clinical chemistry was performed weekly. patients. One patient was not included in the evaluation because Creatinine Cl and dipstick urinalysis were assessed on day 1 of he had both impaired renal function and impaired liver function. the subsequent cycles, whereas the audiogram was repeated at The characteristics of all 25 patients are listed in Tables 1 and 2. the end of every third cycle. The study was performed according to the rules of the declara- Grading of toxicity was scored according to the WHO tion of Helsinki and was approved by the medical ethical com- criteria. A new treatment cycle could not be started until the mittee of the Hospital Vrije Universiteit. patient had recovered from adverse events associated with a Lobaplatin for injection was supplied by ASTA Medica prior treatment cycle. Recovery had occurred when the leuko- AG (Frankfurt, Germany) as a sterile lyophilized powder (50 cyte count was Ն3.0 ϫ 109/liter, the neutrophil count was mg/vial). The drug was reconstituted with 5 ml of 0.9% NaCl. Ն1.5 ϫ 109/liter, and the platelet count was Ն150 ϫ 109/liter.

Table 2 Patient starting dose and biochemistry values Creatinine Cl Body Serum creatinine Dose surface concentration Cockcroft Urine sampling Bilirubin ␥-GT ASAT ALAT Patient no. (mg/m2) (m2) (␮mol/liter) (ml/min/1.73 m2) (␮mol/liter) (units/liter) (units/liter) (units/liter) Group 001 50 1.90 80 88 107 6 35 21 21 Na 010 50 1.92 105 79 79 10 11 12 16 N 014 50 1.55 75 64 108 6 15 12 7 N 015 50 1.92 81 80 96 4 15 14 10 N 017 50 1.70 69 89 NDb 5131320N 018 40 1.54 78 61 87 5 39 7 5 N 002 50 1.90 83 73 101 15 267 24 10 L 003 50 1.83 75 82 ND 8 94 29 32 L 004 50 1.48 62 85 88 8 222 44 18 L 006 50 1.85 85 76 79 10 167 35 17 L 008 50 2.10 87 81 84 8 77 34 62 L 013 50 1.80 100 80 ND 4 44 35 68 L 007 50 1.82 77 67 67 5 13 8 7 RI 009 50 1.98 118 59 48 5 32 8 2 RI 019 50 1.74 114 54 62 6 14 14 10 RI 021 40 2.02 144 52 58 12 24 11 10 RI 022 40 1.58 120 49 78 6 11 10 6 RI 025 40 1.82 100 71 65 5 33 10 10 RI 012 40 1.80 138 50 51 6 10 10 5 RII 011 40 1.98 171 38 22 4 26 28 28 RII 016 40 1.56 124 37 40 3 14 11 9 RII 020 30 1.54 138 37 33 5 33 12 9 RII 023 40 1.48 120 53 51 4 ND 10 13 RII 024 30 1.63 191 26 28 7 18 12 11 RII 005 50 2.11 134 52 ND 17 338 30 35 L/RI a N, normal; L, impaired liver function, RI, impaired renal function level I; RII, impaired renal function level II. b ND, not determined.

Assessment of efficacy, where applicable, was performed every Urine was collected before and up to 48 h after the first second or third cycle. Response to treatment was classified bolus injection and during the second and third cycle (before according to the WHO criteria. A complete response was de- and up to 24 h after the bolus injection). After determination of fined as complete disappearance of all measurable and evaluable the volume, aliquots were stored at Ϫ20°C. disease over a period of at least 4 weeks. A partial remission was Analysis. The amount of platinum in the plasma (total defined as at least a 50% decrease of the sum of the products of platinum), plasma ultrafiltrate (ultrafilterable platinum), urine, the largest perpendicular lesion diameters without the appear- and erythrocytes was determined by flameless atomic absorp- ance of new lesions over a period of at least 4 weeks. No change tion spectrophotometry. Samples of plasma, plasma ultrafiltrate, was defined as a change from baseline within the limits of a and urine were diluted 2.5 times with a solution of 0.9% sodium 50% regression or a 25% increase of lesion area. Disease pro- chloride and 0.2 M hydrochloric acid. Samples of erythrocytes gression was defined as a 25% or greater increase in the size of (200 mg) were digested with hyamine hydroxide (500 ␮l) by one or more measurable or evaluable lesions. incubation in a heating bath (55°C) for approximately 15 h. Sampling. During the first course, blood samples were Thereafter, the mixture was diluted with 4.25 ml of hydrochloric obtained before and at 0 (just after bolus injection), 5, 15, and 30 acid solution (0.2 M). Calibration standards and quality control min and 1, 2, 4, 6, 9, 11, 22, 24, 48, 72, 96, and 120 h after bolus samples were prepared in plasma, plasma ultrafiltrate, and urine injection. For the second and third cycle, a reduced number of by spiking the matrix with a solution of lobaplatin in 0.9% blood samples were taken up to 6 h after drug administration. sodium chloride and 0.2 M hydrochloric acid. The injection ␮ Samples were collected in NH4-heparin-coated tubes and cen- volume was 10 l. For erythrocytes, the matrix was spiked with trifuged immediately for 10 min at 1,500 ϫ g and 15°C. After a solution of lobaplatin in water. The injection volume was 2 removing the plasma, the erythrocyte fraction was washed with times 20 ␮l. The furnace program of the flameless atomic sodium phosphate buffer (pH 7.4). Four ml of the plasma were absorption spectrophotometry method consisted of a drying step immediately transferred into a centriflo ultrafiltration membrane between 100°C and 150°C, followed by ashing at 1300°C. Ͼ cone (CF 25; size exclusion limit of the membrane, Mr Platinum was evaporated at 2600°C and measured with a plat- 25,000; Amicon, Beverly, MA) and centrifuged for 45 min at inum cathode lamp at a wavelength of 266 nm. The method was 1,000 ϫ g and 15°C. For the analysis of the diastereoisomers of validated by determining the between-day accuracy and preci- lobaplatin, 1.5 ml of plasma ultrafiltrate was stored at Ϫ80°C in sion of the quality control samples analyzed at three concentra- polypropylene test tubes. For the analysis of platinum in plasma, tion levels in duplicate on six different days. The within-day plasma ultrafiltrate and erythrocytes samples were stored at accuracy and precision were determined by analyzing the qual- Ϫ20°C in polypropylene test tubes. ity control samples in 6-fold on one day. The lower limit of

quantification (inaccuracy and precision Ͻ 20%) was 0.19 ␮M criterion, as well as the consideration of a random distribution of for platinum in plasma, plasma ultrafiltrate, and urine and 0.54 the signs of the residuals (12). ␮M for platinum in erythrocytes. The accuracy and precision of The platinum excretion in the urine was expressed as the the analysis at the highest concentration of the calibration lines total amount of platinum excreted in the urine as a percentage of (5.42 ␮M) were 99.6 and 5.3%, 99.1 and 2.0%, 100.8 and 5.4%, the dose (Ae). and 102.2 and 4.1% for platinum in plasma, plasma ultrafiltrate, To investigate the role of erythrocytes as a possible deep urine, and erythrocytes, respectively. The inaccuracy and preci- pharmacokinetic compartment and its consequence for the inci- sion of the quality control samples were less than 10%. To dence of anemia, the uptake of platinum in RBCs (as a percent- determine low platinum concentrations (Ͻ0.19 ␮M) in plasma age of the dose) was also calculated (blood volume ϫ hemato- and plasma ultrafiltrate, a larger amount of sample was injected crit ϫ platinum concentration in RBCs ϫ 100%/total dose into the graphite furnace (2 times 20 ␮l), and the furnace administered, in which the blood volume was estimated to be program was adjusted by increasing the time for drying and 7.7% of the body weight of the patient). ashing of the sample in the furnace. The lower limit of quanti- Pharmacodynamics. The dose-limiting toxicity of fication was 0.05 ␮M, and the accuracy and precision of the lobaplatin is thrombocytopenia. Platelet counts were used to analysis at the highest concentration of the calibration lines calculate the thrombocyte SF, which is defined by the relative (0.60 ␮M) was 99.5 and 3.9% and 99.5 and 1.0% for platinum in thrombocyte nadir divided by the thrombocyte count on day 0 plasma and plasma ultrafiltrate, respectively. (just before bolus injection). Because most biological effects The two diastereoisomers of lobaplatin (LP-D1 and LP- such as the SF of blood cells will vary exponentially with a D2) in plasma ultrafiltrate were analyzed according to the high- parametric change, the following equation was used (13): log performance liquid chromatography method described by our SF ϭ k ϫ AUC. From this equation, a linear relationship may group (11). In short, lobaplatin was isolated from plasma ultra- be expected between logSF and the AUC. filtrate by a solid-phase extraction procedure (C18 cartridge), Before treatment with lobaplatin, the creatinine Cl was separated into the individual diastereoisomers by a reverse- calculated from the creatinine concentration in the 24 h urine phase high-performance liquid chromatography column (Hyper- sample and the serum creatinine concentration [Cl ϭ urine sil ODS), and detected by UV absorption at 210 nm. Calibration creatinine (mmol/day) ϫ 1000/1440 ϫ serum creatinine (␮mol/ standards and quality control samples were freshly prepared by liter)] or from the serum creatinine concentration alone by the spiking human plasma ultrafiltrate with an aqueous solution of Cockcroft formula [Ref. 14; Cl ϭ K ϫ (140 Ϫ age) ϫ weight lobaplatin and a subsequent dilution of this sample with plasma (kg)/serum creatinine (␮mol), in which K ϭ 1.05 for females ultrafiltrate. The lower limit of quantification was 0.071 ␮M for and 1.23 for males]. LP-D1 and 0.067 ␮M for LP-D2. The accuracy and precision of the analysis at the highest concentration of the calibration lines (9.100 ␮M for LP-D1 and 8.639 ␮M for LP-D2) were 104.4 and RESULTS 2.0% and 103.3 and 1.9% for LP-D1 and LP-D2, respectively. Response. Nineteen patients received at least two cycles Pharmacokinetics. Pharmacokinetic parameters were of lobaplatin, and 13 of these patients showed progressive calculated by noncompartmental analysis using the pharmaco- disease. The five patients for whom no change was recorded kinetic software TopFit, Version 2.0 (12). Pharmacokinetic pa- received 4–10 cycles (median, six cycles). Of interest, one rameters were calculated according to standard procedures. The patient with a local recurrence of squamous cell carcinoma in AUCϱ in the noncompartment model was calculated by the the oropharyngeal area had a clinical partial remission after two linear trapezoidal rule with an extrapolation of the final log- cycles that was complete after five cycles. Unfortunately, this ϱ ϭ ϩ linear part of the C-t curve to infinity: AUC AUC0 3 t patient died of pneumonia and bleeding from erosive gastritis Clast/t1/2 final, in which Clast is the last detectable concentration, after the sixth cycle of lobaplatin. An autopsy revealed the and t1/2 final is the final half-life. Subsequent calculations were as presence of a second primary tumor, colon cancer, with perito- follows: total body Cl ϭ D/AUCϱ and MRT ϭ AUMCϱ/AUCϱ, neal spread and liver metastases, without evidence of local in which AUMCϱ represents the area under the (first) moment recurrence of oropharyngeal cancer. ϱ ϭ ϩ ϫ curve, calculated by the formula AUMC AUMC0 3 t t Toxicity. For the first 11 patients that entered the proto- ϩ 2 Clast/t1/2 final Clast/(t1/2 final) . The steady-state apparent vol- col, antiemetic treatment was not routinely given before the ϭ ϫ ume of distribution is as follows: Vss Cl MRT. Student’s t administration of lobaplatin. Because patients were hospitalized test (two-tailed distribution and two-sample equal variance) was for their participation in the pharmacokinetic study, ondanse- used for the statistical evaluation of the differences between the trone (8 mg, i.v.) could be administered immediately upon mean values calculated for the patient groups. vomiting. All patients needed antiemetic treatment. Prophylaxis To compare the pharmacokinetics of lobaplatin with earlier was given routinely in further cycles as well as in subsequent data of other platinum compounds and to calculate initial half- patients from cycle 1 onward. Patients usually recovered from lives, the C-t curves were also fitted with the NONLIN program nausea and vomiting within 24 h. In those cases where prophy- TOPFIT, Version 2.0 (12) using the biexponential equation laxis was not complete, ondansetrone (8 mg) or metoclopramide ϭ ϫ Ϫ␣t ϩ ϫ Ϫ␤t ϭ Ct A e B e and the triexponential equation Ct (10 mg) by oral route was prescribed. Other nonhematological A ϫ eϪ␣t ϩ B ϫ eϪ␤t ϩ C ϫ eϪ␥t, respectively. The statistics toxicities were mild and consisted of grade 1–2 stomatitis (four used to determine the best fit included the sum of the squares of patients), grade 1 alopecia (one patient), grade 1–2 paresthesias the weighted or unweighted residuals, using the F-ratio test, (three patients), and grade 1–2 anorexial (five patients). Eight Akaike information criterion, Swarz criterion, and imbimbo patients experienced grade 1–2, fatigue and four patients expe-

Table 3 Numbers of patients with hematological toxicity in cycles 1 and 2a Leukopenia Neutropenia Thrombocytopenia Anemia Delay Ն 1 week Dose reduction Group Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Cycle 2 Cycle 3 Cycle 2 Cycle 3 Normal 1 1 3 3 3/5 3/3 2/5 1/3 Liver 1 1113 51 2/50/10/50/1 Renal I 1 3 1 1 4 5 2/5 2/3 1/5 1/3 Renal II 2123 5 3214/41/34/43/3 a WHO criteria: leukopenia grade 3, 1.0–1.9 ϫ 109/liter; leukopenia grade 4, Ͻ1.0 ϫ 109/liter; neutropenia grade 3, 0.5–0.9 ϫ 109/liter; neutropenia grade 4, Ͻ0.5 ϫ 109/liter; thrombocytopenia grade 3, 25.0–49.9 ϫ 109/liter; thrombocytopenia grade 4, Ͻ25.0 ϫ 109/liter; anemia grade 3, Hb 4.0–4.9 mmol/liter; anemia grade 4, Hb Ͻ 4.0 mmol/liter.

rienced grade 3, fatigue which usually occurred in the presence became lower than total platinum concentrations over time. of anemia. After 11 h, about 60% of the circulating platinum was bound to Hematological toxicity was considerable, and thrombocy- plasma proteins. The C-t curves of the diastereoisomers LP-D1 topenia was the most prominent toxicity (Table 3). Nadirs of and LP-D2 were superimposable, as were those of ultrafilterable blood counts were observed between days 14 and 16 after platinum and intact lobaplatin. Similar results were obtained for lobaplatin administration. The majority of patients experienced the other patient groups. grade 4 thrombocytopenia, which was why we monitored blood The influence of renal and liver function on pharmacoki- counts around the expected nadir value every second to third netics is shown in Fig. 3 by the C-t curves of total platinum and day until recovery. Recovery was rapid except in patients with ultrafilterable platinum for the four patient groups. Impaired impaired renal function, in whom grade 4 toxicity could be liver function within the investigated range did not affect the C-t present for as long as 1 week. Prophylactic platelet transfusions curves of total platinum or ultrafilterable platinum. In contrast, were given (when the platelet count decreased to Ͻ10 ϫ 109/ the concentration of these platinum species became higher when liter) in one of six patients with level I and five of six patients the renal function became lower. Table 4 gives a summary of the with level II impaired renal function in the first two cycles of pharmacokinetic parameters of platinum in plasma and plasma lobaplatin treatment. In 16 patients, Hb fell below 6.0 mmol/liter ultrafiltrate and the pharmacokinetic data of the diastereoiso- (97 g/dl), which was the reason for erythrocyte transfusions. mers LP-D1 and LP-D2 and intact lobaplatin (LP-D1 ϩ LP-D2) Only two patients presented with overt bleeding, one because of in plasma ultrafiltrate. All parameters have been determined by vaginal blood loss in the presence of pelvic disease of colon noncompartmental analysis of the C-t data. For the patient group cancer (thrombocytopenia grade 1), and the other because of with impaired renal function level II, only four patients could be rectal blood loss in the presence of a local recurrence of ovarian evaluated for intact lobaplatin because of interfering endoge- cancer (thrombocytopenia grade 4). One patient with grade 4 nous substances in the chromatograms. Table 5 shows the cu- leukopenia in the first cycle had a fever of unknown origin and mulative urinary platinum excretion up to 48 h after the bolus was treated with antibiotics. In the second lobaplatin cycle, injection of lobaplatin. Ϯ fever recurred in this patient, and Klebsiella pneumoniae was The t1/2 final of total platinum in plasma was 6.8 4.3 days, demonstrated to be the causative agent. measured from 1–5 days after administration. No difference was

As can be deduced from Table 3, in 11 of 19 patients, observed in the t1/2 final of total platinum between the different lobaplatin cycle 2 had to be delayed because recovery from patient groups. Also, no difference was detected between the myelosuppressive side effects was not complete. The protocol values of the pharmacokinetic parameters of the patient group required a dose reduction of 10 mg/m2 in case of grade 4 with normal liver and renal function and the group with an hematological toxicity of Ͼ7 days in duration. Because of the impaired liver function. An increase in the AUC/D was meas- high incidence of grade 4 thrombocytopenia for Ͻ7 days, the ured in the patient groups with impaired renal function level I requirement of erythrocyte transfusions, and the delay of further (P ϭ 0.03), which was more pronounced for the patients with treatment, it was decided from the ninth patient onward to level II renal impairment (P ϭ 0.02). This increase corre- 2 ϭ reduce the dose of lobaplatin by 10 mg/m in case of grade 4 sponded with a decrease in the total body Cl (P 0.02), Vss ϭ ϭ thrombocytopenia of any duration as well as in all first cycles of (P 0.07), and Ae(0–24 h) (P 0.3) and was also more patients with impaired renal function (Table 2). Some patients pronounced for the patients with level II renal impairment (P ϭ required additional dose reductions upon later cycles. 0.004, P ϭ 0.01, and P ϭ 0.001, respectively). No statistically Pharmacokinetics. The semilogarithmic plots of the significant differences were observed between the pharmacoki- mean C-t curves of total platinum, ultrafilterable platinum, the netic data of patients with impaired renal function level I and diastereoisomers LP-D1 and LP-D2, and intact lobaplatin for the level II (P ϭ 0.1). group of patients with normal renal and liver function are shown For ultrafilterable platinum, the t1/2 final was much shorter in Fig. 2. Total platinum (protein-bound platinum ϩ ultrafilter- (131 Ϯ 15 min, measured from 2–11 h) than that of total able platinum) could still be measured after 5 days, whereas platinum. No differences were observed between the pharma- ultrafilterable platinum and intact lobaplatin could only be cokinetics of the patient group with normal liver and renal measured for up to 11 h after the administration of lobaplatin. function and the group with impaired liver function. An im- Due to protein binding, ultrafilterable platinum concentrations paired renal function level I, however, resulted in an increase of

Fig. 2 Semilogarithmic plot of the mean C-t curves of platinum in plasma and plasma ultrafiltrate and intact lobaplatin (LP-D1 and LP-D2) in plasma ultrafiltrate in the patient group with normal liver and renal function (n ϭ 6); A,upto30h;B,upto120h.

Յ the t1/2 final (P 0.001) that corresponded with an increase in third cycle on the basis of grade 4 thrombocytopenia in the the AUC/D (P Յ 0.001) and MRT (P Յ 0.001) and a decrease preceding cycle. in Cl (P Յ 0.001). This was more pronounced for the patients The best NONLIN fits of the plasma C-t curves of total with level II renal impairment. Between patients with renal platinum and ultrafilterable platinum for the patient group with impairment level I and level II, a statistically significant differ- normal renal and liver function were obtained with a triexpo- ϭ ϭ ence was observed for the t1/2 final (P 0.004), AUC/D (P nential function and a biexponential function, respectively. The 0.007), MRT (P ϭ 0.005), and Cl (P ϭ 0.01). resulting values of the pharmacokinetic parameters were similar No differences were seen between the values of the diaste- to the values obtained with the noncompartmental analysis. The reoisomers LP-D1 and LP-D2 and between the values for intact mean initial half-lives obtained were 9.2 Ϯ 6.8 and 119 Ϯ 36 Ϯ lobaplatin and ultrafilterable platinum, as shown in Fig. 2. min for t1/2␣ and t1/2␤ of total platinum, respectively, and 14.6 Changes in these values due to differences in renal function 3.1 min for t1/2␣ of ultrafilterable platinum. between the groups were comparable to those observed for Platinum was taken up in erythrocytes. In patients with

ultrafilterable platinum. normal renal and liver function, maximum levels (Cmax)of Ϯ ␮ Ϯ Most of the platinum was excreted in the urine within the 2.1 0.4 M were reached at about3h(Tmax, 3.2 0.7 h) after first 6 h after drug administration (Table 5). For patients with bolus injection. At that time, ultrafilterable platinum levels in impaired renal function, the decrease in platinum excretion is plasma were still about 1.5 times higher than those in erythro- explained by the difference in the first 6 h. cytes. At the time of the maximum concentration, about 1.7% of

To check for changes in the pharmacokinetics between the dose was present in erythrocytes. The t1/2 final of platinum Ϯ subsequent cycles, values of AUC(0–6h) normalized to a dose of present in erythrocytes was 11 7 days as measured over days 50 mg/m2 were calculated. No differences were observed for the 1–5. Comparable values were obtained for the patients with

pharmacokinetics between the subsequent cycles. AUC(0–6 h) impaired liver function. In patients with impaired renal function, Ϯ ␮ decreased linearly when the dose was reduced in a second or Cmax increased nonsignificantly to 2.5 0.5 M (representing

Fig. 3 Semilogarithmic plot of the mean C-t curves of total platinum (A) and ultrafilterable platinum (B) in patients with normal liver and renal function (n ϭ 6), with impaired liver function (n ϭ 6), and with impaired renal function level I (n ϭ 6) and level II (n ϭ 6).

2.2% of the dose at that moment) for level I and to 2.8 Ϯ 0.8 ␮M calculated by the Cockcroft formula [correlation coefficient, ϭ ϱ ϩ (representing 2.1% of the dose at that moment) for level II. Tmax 0.85; dosage formula, D AUC (1.5 ClCrC 3)]. These increased significantly [level I, 4.8 Ϯ 1.3h(P ϭ 0.03); level II, formulas can be used to calculate a tolerable dose for each Ϯ ϭ 2 4.6 1.1h(P 0.03)]. The t1/2 final of platinum in erythrocytes individual patient with a creatinine Cl of Ն30 ml/min/1.73 m did not change in relation to renal function. by selecting the target AUC that belongs to a desired degree of Nadirs of thrombocytes were reached between 14 and 16 thrombocytopenia. days after the administration of lobaplatin. Therefore, the SF of the thrombocytes was calculated in each patient on day 14 or close to this time. A linear relationship was found between log DISCUSSION SF and the AUCϱ of ultrafilterable platinum. The correlation Antineoplastic drugs generally have a narrow therapeutic win- coefficient was 0.72 (Fig. 4, cycle 1). In all patients, preceding dow. However, the plasma levels of a certain drug at which toxicity cycles of lobaplatin resulted in cumulative thrombocytopenia or therapeutic effects occur may vary from patient to patient. (lowering of the lines in Fig. 4, cycles 2 and 3). Therefore, cancer chemotherapy may be optimized by individual- The values in Table 4 show that the total body Cl of izing a patient’s therapy using individual calculations. To achieve ultrafilterable platinum (ClUFPt) was dependent on the renal this goal, it is necessary to establish pharmacokinetic-pharmacody- function. When ClUFPt was plotted against the creatinine Cl, as namic relationships for each anticancer drug. This will allow the calculated from the creatinine concentration in the 24 h urine calculation of the optimal dose for a given patient to obtain a samples (ClCrU), a good linear relationship (correlation coeffi- defined acceptable level of toxicity and the highest individual ϭ ϩ cient, 0.91) was obtained [ClUFPt 1.1 ClCrU 16 (Fig. 5)]. therapeutic effect. It is much more complicated to establish a ϱ Substituting ClUFPt with D/AUC resulting in the following relationship between pharmacokinetics and treatment response than ϭ ϱ ϩ formula for the dose (Dg mg): D AUC (1.1 ClCrU 16). A it is to establish a relationship between pharmacokinetics and side comparable result was obtained when the creatinine Cl was effects. Often the degree of toxicity is related to the AUC or Css of

Table 4 Mean pharmacokinetic data of lobaplatin after i.v. bolus injection calculated by noncompartmental analysis Cl

AUC/D (ml/min) Vss a ⅐ 2 2 Patient group t1/2 final (min m /liter) (1.73 m ) MRT (h) (liters/kg) A. Total platinum

Normal (n ϭ 6) 6.8 Ϯ 4.3 days 57.0 Ϯ 18.6 34 Ϯ 11 174 Ϯ 129 4.8 Ϯ 2.6 Impaired liver (n ϭ 6) 4.5 Ϯ 0.7 days 43.4 Ϯ 7.0 41 Ϯ 8 105 Ϯ 21 3.9 Ϯ 1.0 Impaired renal I (n ϭ 6) 6.1 Ϯ 4.3 days 91.6 Ϯ 26.6 20 Ϯ 5 165 Ϯ 137 2.4 Ϯ 1.4 Impaired renal II (n ϭ 6) 5.1 Ϯ 2.7 days 136.4 Ϯ 70.8 15 Ϯ 7 142 Ϯ 93 1.5 Ϯ 0.3

B. Ultrafilterable platinum

Normal (n ϭ 6) 131 Ϯ 15 min 13.9 Ϯ 1.8 125 Ϯ 14 2.4 Ϯ 0.3 0.28 Ϯ 0.05 Impaired liver (n ϭ 6) 151 Ϯ 6 min 13.7 Ϯ 2.9 113 Ϯ 31 2.8 Ϯ 0.2 0.33 Ϯ 0.09 Impaired renal I (n ϭ 6) 183 Ϯ 19 min 22.1 Ϯ 3.3 78 Ϯ 11 3.7 Ϯ 0.5 0.25 Ϯ 0.02 Impaired renal II (n ϭ 6) 235 Ϯ 28 min 31.4 Ϯ 5.9 58 Ϯ 11 4.9 Ϯ 0.7 0.26 Ϯ 0.05

C. LP-D1

Normal (n ϭ 6) 132 Ϯ 14 min 7.0 Ϯ 1.0 126 Ϯ 16 2.3 Ϯ 0.3 0.28 Ϯ 0.04 Impaired liver (n ϭ 6) 151 Ϯ 14 min 6.6 Ϯ 1.2 134 Ϯ 24 2.7 Ϯ 0.3 0.33 Ϯ 0.09 Impaired renal I (n ϭ 6) 182 Ϯ 18 min 10.6 Ϯ 1.6 81 Ϯ 11 3.6 Ϯ 0.5 0.25 Ϯ 0.02 Impaired renal II (n ϭ 4) 233 Ϯ 28 min 16.1 Ϯ 2.9 56 Ϯ 12 4.7 Ϯ 0.6 0.22 Ϯ 0.03

D. LP-D2

Normal (n ϭ 6) 133 Ϯ 18 min 6.7 Ϯ 1.0 132 Ϯ 16 2.4 Ϯ 0.3 0.29 Ϯ 0.04 Impaired liver (n ϭ 6) 151 Ϯ 11 min 6.4 Ϯ 1.4 140 Ϯ 28 2.7 Ϯ 0.2 0.36 Ϯ 0.12 Impaired renal I (n ϭ 6) 181 Ϯ 20 min 10.2 Ϯ 1.6 85 Ϯ 13 3.6 Ϯ 0.5 0.26 Ϯ 0.02 Impaired renal II (n ϭ 4) 237 Ϯ 31 min 15.9 Ϯ 3.5 57 Ϯ 15 4.8 Ϯ 0.7 0.23 Ϯ 0.02

E. Intact lobaplatin

Normal (n ϭ 6) 132 Ϯ 16 min 13.6 Ϯ 2.0 128 Ϯ 16 2.4 Ϯ 0.3 0.28 Ϯ 0.04 Impaired liver (n ϭ 6) 152 Ϯ 13 min 12.9 Ϯ 2.6 137 Ϯ 25 2.7 Ϯ 0.2 0.34 Ϯ 0.09 Impaired renal I (n ϭ 6) 182 Ϯ 19 min 20.7 Ϯ 3.2 82 Ϯ 12 3.6 Ϯ 0.5 0.26 Ϯ 0.02 Impaired renal II (n ϭ 4) 246 Ϯ 44 min 35.0 Ϯ 9.5 54 Ϯ 17 5.0 Ϯ 1.0 0.22 Ϯ 0.02 a t1/2 final was calculated over the following time periods: total platinum, 1–5 days; ultrafilterable platinum, 2–11 h; LP-D1, 2–11 h; LP-D2, 2–11 h; and intact lobaplatin, 2–11 h.

Table 5 Cumulative amount of platinum excreted in the urine (Ae) after i.v. bolus injection of lobaplatin, expressed as a percentage of the dose (% D) Patient group Ae (0–6 h) Ae (0–12 h) Ae (0–24 h) Ae (0–48 h) Normal 58.3 Ϯ 6.9 67.1 Ϯ 9.1 69.6 Ϯ 9.9 70.1 Ϯ 8.8 Impaired liver 55.2 Ϯ 10.0 66.2 Ϯ 10.0 70.0 Ϯ 10.4 73.2 Ϯ 10.9 Impaired renal I 46.2 Ϯ 13.4 55.0 Ϯ 15.1 60.9 Ϯ 15.1 64.2 Ϯ 17.2 Impaired renal II 27.9 Ϯ 10.7 41.0 Ϯ 9.8 49.1 Ϯ 5.6 53.6 Ϯ 5.1

a drug (15). The first onset for a pharmacokinetic-toxicity relation- lobaplatin, leading to a dosage formula that allows the individual- ship can be obtained during a Phase I study, after which an ization of the lobaplatin dose. extension or a confirmation of the relationship can be obtained The pharmacokinetic results showed that the C-t curves of during the following Phase II or, if desired, phase III studies. Using total platinum (protein bound platinum ϩ ultrafilterable platinum), such a relationship, it becomes possible to administer the highest ultrafilterable platinum, and intact lobaplatin were similar during possible dose to obtain the highest possible therapeutic effect in an the first few hours after an i.v. bolus injection of lobaplatin. There- individual patient. As soon as a pharmacokinetic-therapeutic effect after, the concentrations for ultrafilterable platinum and intact relationship can be established, and it appears that an optimal lobaplatin were lower than those of total platinum, indicating that therapeutic effect can be obtained at a lower dose level, individual protein binding only takes place slowly. This is in agreement with therapeutic windows are obtained. In the present study, we estab- our in vitro data (obtained according to Ref. 16), which revealed lished pharmacokinetic-pharmacodynamic relationships for that only 6% of lobaplatin was bound to human plasma proteins for

Fig. 4 Semilogarithmic plot of the thrombocyte SFs versus the AUC of ultrafilterable platinum after the first, second, and third course.

with impaired renal function, which was more pronounced for patients with level II impairment. The high Ae values indicate that urinary platinum excretion is the major route of elimination. Therefore, impaired renal function will have a major impact on the elimination of platinum from the body, which corresponds to a lower total body Cl and higher AUC and MRT values. No differences were observed between the pharmacokinetics of ultrafilterable platinum and intact lobaplatin (LP-D1 plus LP- D2). This means that all free platinum exists as intact lobaplatin, indicating that no metabolites were formed up to the lowest measured concentration of intact lobaplatin (0.14 ␮M). Also, the phar- Fig. 5 Total body Cl of ultrafilterable platinum (UFPt) versus creati- macokinetics of the two diastereoisomers, LP-D1 and LP-D2, were nine Cl (urine sampling). similar, indicating that the difference in the molecular configuration has no influence on the pharmacokinetics. From the pharmacokinetic data obtained during successive courses in which the dose was lowered in some patients, it after2hofincubation. After 8 and 24 h, this percentage increased appeared that the AUC(0–6 h) was linearly related with the dose to 16% and 33%, respectively. This also means that the centrifu- within the considered dose range of 20–50 mg/m2. No differ- gation time needed to obtain plasma ultrafiltrate did not influence ences were found between the pharmacokinetic parameters of the concentration of ultrafilterable platinum. Ultrafilterable plati- successive courses. This corresponds with the lack of influence num was detectable in the circulation for 11 h in patients with of lobaplatin on the renal function, which remained constant normal liver and renal function and for up to 96 h in patients with during a cycle and between cycles. impaired renal function. During this longer period of time, the Previous pharmacokinetic data on lobaplatin (6, 10) corre- composition of ultrafilterable platinum may also be changed. Total spond with our findings, except for the t1/2 final and the urinary platinum concentrations measured after these periods represent platinum excretion. Gietema et al. (6) have measured shorter lobaplatin that has reacted with plasma proteins. These protein- final half-lives for total platinum and ultrafilterable platinum, bound platinum species are eliminated from the body with slow although lobaplatin was also given as an i.v. bolus injection elimination rates, which correspond to the turnover rates of the (30–50 mg/m2). The difference can be explained by the shorter Ͻ plasma proteins. This explains why the t1/2 final of total platinum is sampling period of their pharmacokinetic study ( 11 h). The less sensitive for changes in renal function than the free platinum urinary platinum excretion over the first 24 h in that study was species. 73 Ϯ 4% of the administered dose, which is in accordance with The final half-lives of ultrafilterable platinum were similar our findings (70 Ϯ 10% D). In contrast, Mross et al. (10) have for the patients with normal liver and renal function and the measured only 26 Ϯ 8% of the dose excreted in the urine during patients with impaired liver function. An increase was detected the first 48 h after the administration of lobaplatin as an i.v. in patients with impaired renal function, which was more pro- bolus injection (20–50 mg/m2). No explanation can be given for Ϯ nounced for patients with level II impairment. These differences this difference. Also a shorter t1/2 final for total platinum (1.4 are in agreement with the amounts of platinum excreted in the 1.4 days) was calculated that might be due to blood sampling for urine, i.e., no difference in Ae(0–24 h) was seen between patients only 2 days instead of 5 days in our study. with normal liver and renal function and patients with impaired Similarities are observed between the pharmacokinetics of liver function, but a decrease in Ae(0–24 h) was seen in patients lobaplatin and carboplatin (17). For carboplatin, the urinary

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Jan Welink, Epie Boven, Jan B. Vermorken, et al.

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