Total Plasma Platinum Research Articles

Using HPLC for the determination of platinum drugs in biological matrixes after derivatization with diethyldithiocarbamate.

Challenges and pitfalls in the application of diethyldithiocarbamate derivatization for LC analysis of cisplatin and oxaliplatin, as well as the suitability of this method for different biological matrices with implications for use in routine practice have been identified. The LC of platinum drugs presents a significant challenge. They are polar compounds with poor retention on reverse phase packings. Cisplatin also exhibits poor absorption in UV and ionization in mass spectrometry. Therefore, we developed and optimized a derivatization approach for the LC analysis of total platinum in plasma, plasma ultrafiltrate, peritoneal fluid, and urine. Derivatization in urine proved to be difficult due to the complexity of the matrix, and extended testing was required. Our results highlight the important issues affecting the efficiency, reliability, and suitability of platinum drug derivatization. Although precolumn derivatization is less selective than its postcolumn counterpart, the application of precolumn derivatization is a simple, rapid, and universal approach for the determination of platinum drugs by HPLC. One of its major advantages is that it allows a more affordable analysis using UV detection without the need for additional high-end instrumentation such as a MS detector.

Abstract 5060: Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study

Abstract Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5060.

Characterization and Pharmacokinetic Evaluation of Oxaliplatin Long-Circulating Liposomes.

The clinical efficacy of Oxaliplatin (L-OHP) is potentially limited by dose-dependent neurotoxicity and high partitioning to erythrocytes in vivo. Long-circulating liposomes could improve the pharmacokinetic profile of L-OHP and thus enhance its therapeutic efficacy and reduce its toxicity. The purpose of this study was to prepare L-OHP long-circulating liposomes (L-OHP PEG lip) by reverse-phase evaporation method (REV) and investigate their pharmacokinetic behavior based on total platinum in rat plasma using atomic absorption spectrometry (AAS). A simple and a sensitive AAS method was developed and validated to determine the total platinum originated from L-OHP liposomes in plasma. Furthermore, long-circulating liposomes were fully characterized in vitro and showed great stability when stored at 4°C for one month. The results showed that the total platinum in plasma of L-OHP long-circulating liposomes displayed a biexponential pharmacokinetic profile with five folds higher bioavailability and longer distribution half-life compared to L-OHP solution. Thus, long-circulating liposomes prolonged L-OHP circulation time and may present a potential candidate for its tumor delivery. Conclusively, the developed AAS method could serve as a reference to investigate the pharmacokinetic behavior of total platinum in biological matrices for other L-OHP delivery systems.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75mg/m2]. Blood was collected pre-dose and up to 6h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2h also correlated with urinary clusterin, β2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000ng/ml, and peak urinary platinum concentrations above 24,000ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study.

The objectives of this study were to assess the pharmacokinetics and safety of subcutaneously delivered carboplatin in poloxamer 407 in rats. Carboplatin (5mg/rat) in 0.5ml poloxamer 407 (1.0 ml total volume) was administered subcutaneously in a right subcutaneous perineal incision in all 12 treatment rats. Three control rats received 1.0 ml of poloxamer 407. Total platinum was measured in plasma q24hrs from 0 to 168hrs. Protein-unbound platinum was measured in plasma at 168hrs. After sacrifice on day 7, total platinum was determined in wound bed muscle. Platinum concentrations in all samples were measured by ICP-MS. Wounds were visually assessed daily for 7 days. Perineal tissues (full wound bed including muscle, subcutis, skin) were assessed histologically and scored. Total platinum was detectable in plasma from 24 to 168 hrs. Total plasma platinum AUC and Cmax were 9,165.3 ng/mL•h and 129.4 ng/mL. Day 7 total platinum concentration in muscle was approximately 10-fold higher than total plasma platinum concentration. No unbound platinum was detected in plasma samples at 168 hours. No wound healing complications were detected at any time point, nor was tissue necrosis observed histologically. The results of this study suggest that subcutaneous carboplatin in poloxamer 407 can be used in vivo providing direct tissue exposure to carboplatin without significant local effects or systemic absorption and without wound healing complications.

In vivo pharmacokinetic and tissue distribution investigation of sustained-release cisplatin implants in the normal esophageal submucosa of 12 beagle dogs.

The aim of this study was to clarify the pharmacokinetic, tissue distribution, hematologic, and histopathologic characteristics of sustained-release cisplatin from implants [CDDP-nanoparticle (NP) implants]. Eighteen dogs (six hybrids and twelve beagles) were divided into three groups. In Group A, the six hybrid dogs were intravenously administered 20 mg CDDP via a hind limb vein. In Groups B and C, CDDP-NP implants containing CDDP doses of 40 and 60 mg, respectively, were embedded into the esophageal submucosa of beagles via painless gastroscopy with an endoscopic booster. Graphite frameless atomic absorption spectrophotometry was used to measure total platinum in plasma and tissues at various timepoints. In addition, free platinum levels in Group B were determined using inductively coupled plasma mass spectrometry. Toxicologic evaluation was also conducted. Pharmacokinetic results indicated that the CDDP-NP implant could achieve a smooth pharmacokinetic curve, with the plasma invalid concentration reached after almost 480 h, which is approximately ten times longer than that of standard CDDP (48 h). The peak time, peak concentration, clearance, elimination half-life, area under the curve, volume of distribution at steady state, and mean residence time of Groups B and C were 494 and 211, 0.39 and 0.42, 0.044 and 0.059, 80.11 and 87.70, 44 and 49, 38.8 and 57.9, and 12.29 and 12.39 times those of Group A, respectively (all P < 0.05). The ratio of free/total platinum concentration was 2.0-3.1% in plasma, 14.2% in liver tissue, and 14.3% in kidney tissue. Tissue distribution studies showed that the highest platinum concentrations were found in the esophagus, followed by the kidney and liver. Compared with pre-implantation (day 0), there were no significant differences in most hematological indicators in Groups B and C (P > 0.05). Furthermore, histopathologic examination of the kidneys of dogs from Group C revealed no significant kidney damage. Unlike the intravenous CDDP group (Group A), no animals in the implantation groups showed any clinical signs of toxicity. CDDP-NP implants can be used to achieve a smooth pharmacokinetic curve and higher drug concentration, as well as a longer mean residence time at the implantation site, with reduced side effects compared with intravenous CDDP.

In Vivo Evaluation of Cisplatin-loaded Superabsorbent Polymer Microspheres for Use in Chemoembolization of VX2 Liver Tumors

PurposeTo investigate the pharmacokinetics and efficacy of chemoembolization with a cisplatin-loaded superabsorbent polymer (SAP) suspension in a rabbit model with transplanted liver VX2 tumors. Materials and MethodsVX2 tumors were implanted into the left lobe of the liver in eight rabbits. Embolization of the proper hepatic artery was performed with cisplatin-loaded or unloaded SAP. In the cisplatin-loaded SAP group (n = 4), 5 mg of SAP (106–150 μm) loading 2.35 mg of cisplatin and 0.5 mL of ionic contrast material (ioxaglic acid 320 mgI/mL) was injected into the proper hepatic artery. In the control group (hepatic arterial infusion [HAI] + SAP; n = 4), 5 mg of SAP loading 0.5 mL of ioxaglic acid alone was injected after a bolus infusion of an equivalent amount of cisplatin. Sequential change of the plasma platinum concentration within the first 24 hours was measured. Blood sampling and histopathologic examination were performed at 1-week follow-up. Magnetic resonance (MR) images were used to calculate the growth rate of the VX2 tumor. ResultsAll animals underwent successful embolization. Both total and free plasma platinum mean concentrations within the first 24 hours remained lower in the cisplatin-loaded SAP group, although without statistical significance (P > .05). The mean tumor growth rate was significantly lower in the cisplatin-loaded SAP group than the control group (20% vs 116%; P = .049). Histopathologic examination revealed coagulative necrosis to nontumorous liver parenchyma in two rabbits in the cisplatin-loaded SAP group, although no deaths occurred. ConclusionsThese results suggested that chemoembolization with cisplatin-loaded SAP was a safe and tolerable treatment and was more effective in suppressing the tumor growth.

Pharmacokinetics of Oxaliplatin in Gastrointestinal Cancer Patients with Malignant Ascites

The pharmacokinetics of oxaliplatin in plasma and ascitic fluid was investigated in 5 gastrointestinal cancer patients with malignant ascites. Oxaliplatin was administered at 85 mg/m2 by 2-hour infusion in the FOLFOX4 regimen, and the concentrations of total and free platinum were measured. There was a trend of lower plasma Cmax values of total platinum in patients with a larger volume of ascetic fluid. The AUC0-t values of mean concentration curves of total plasma platinum, total ascites platinum, free plasma platinum, and free ascites platinum were 31.15, 7.96, 4.93 and 2.93 μg·h/ml, respectively. The concentrations of free ascites platinum were similar to those of free plasma platinum at the last sampling time of 26 h in each patient. The decrease or disappearance of ascitic fluid was observed in 4 patients. These results suggest that oxaliplatin exerted a beneficial effect in gastrointestinal cancer patients with malignant ascites, even when administered intravenously.

Phase I/II study of the lipiodolization using DDP-H (CDDP powder; IA-call®) in patients with unresectable hepatocellular carcinoma

Lipiodol Ultra-Fluid (Lipiodol(®)), an oily contrast medium, is selectively retained in hepatocellular carcinoma (HCC) through hepatic arterial infusion. DDP-H (IA-call(®)) developed as a CDDP powder, and may be a possible chemotherapeutic agent with lipiodol. We carried out a phase I/II study of the lipiodolization using DPP-H in patients with unresectable HCC. Phase I and pharmacokinetic study: The dose-limiting toxicity (DLT), the maximum tolerance dose (MTD), and the recommended dose (RD) were determined using a modified Fibonacci scheme. The concentration-time profile of total platinum in plasma was analyzed. Phase II study: Thirty-five patients with unresectable HCC received lipiodolization using DDP-H under RD, and the efficacy and safety were assessed. DLT was grade 3 vomiting at 40 mg/m(2). Therefore, MTD and RD were 35 mg/m(2). The peak of total platinum in plasma was over 1.0 μg/ml at 40 mg/m(2) at 30 min after infusion. Of the 35 patients, 16 (45.7%) demonstrated complete responses, and 4 (11.4%) demonstrated partial responses with an additional 9 patients (25.7%) having stable diseases, as assessed by RECIST. Grade 3 thrombocytopenia was found in 1 patient (2.9%), grade 2 hyperbilirubinemia was found in 2 patients (5.7%), and grade 2 vomiting was found in 4 patients (11.4%). Lipiodolization using DDP-H at 35 mg/m(2) is effective and well tolerated in patients with unresectable HCC.

Development and validation of an inductively coupled plasma mass spectrometry method with optimized microwave-assisted sample digestion for the determination of platinum at ultratrace levels in plasma and ultrafiltrate plasma

A highly sensitive inductively coupled plasma mass spectrometry (ICP-MS) method with microwave-assisted sample digestion for the determination of total platinum in rat whole and ultrafiltrate plasma was developed and validated. A first step of this study concerned the optimization of the mineralization procedure, in order to obtain good extraction recovery (higher than 90%) and repeatability (less than 6%) and the absence of matrix effect. ICP-MS analysis was then performed using the “hot plasma/protective ion extraction” mode, achieving high sensitivity and very high signal/noise ratio. Iridium was added as internal standard. The method was then submitted to validation, performed according to the FDA Bioanalytical Validation Methods guidelines and to the Eurachem guide. Validation was carried out in terms of limit of detection (LOD), limit of quantitation (LOQ), linearity, precision, accuracy and stability. An instrumental LOQ of 1.9 ng L −1, corresponding to a concentration of 955 ng L −1 in matrix under the adopted conditions, was obtained, allowing the quantitative analysis of Pt ultratraces. Instrumental linearity was verified in the range 1.9–14,000 ng L −1, corresponding to a concentration range from 955 ng L −1 to 6825 μg L −1 in matrix. Accuracy was evaluated by analyzing control samples for both matrices at different concentration levels; a good agreement (<15%) was obtained. Sample stability was tested by analyzing control samples maintained for 4 h at room temperature or submitted to three freezing–thawing cycles. Finally, the developed method was applied to the analysis of plasma and ultrafiltrate plasma of rats treated with oxaliplatin-base drug, thus demonstrating its reliability in pharmacokinetic studies.

Phase I and pharmacokinetic trial of AP5346, a DACH–platinum–polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients

To determine the maximum tolerated dose (MTD) safety and pharmacokinetics of AP5346, a copolymer-linked 1,2-diaminocyclohexane(DACH)-platinum compound, in advanced solid tumor patients. AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were explored: DL1: 40 mg platinum (Pt)/m2 (1 patient); DL2: 80 (1); DL3: 160 (3); DL4: 320 (3); DL5: 640 (6); DL6: 850 (6); DL7: 1280 (6) mg Pt/m2. Dose-limiting toxicity (DLT) included infusion omission and cycle delay >2 weeks. Twenty-six patients received 41 cycles (median 1/patient, range 1-4). No DLT occurred in DL 1-4; 1 DLT in DL5 (RD; renal insufficiency), two in DL6 (MTD; vomiting; fatigue) and 5 in DL7 (neutropenic infection with diarrhea; neutropenia with vomiting; vomiting with fatigue; renal insufficiency; and fatigue). Two deaths occurred due to renal insufficiency (DL5); in both cases patients had disease in or surrounding genitourinary tract whose contribution could not be accurately discerned. Grade 1-2 creatinine abnormalities occurred in seven patients. Nausea/emesis was frequent (92%), reaching grade 3-4 (23%), but controlled by antiemetics. Grade 2-4 allergic reactions occurred in 4 patients. Cmax and AUC increased linearly with dose for total plasma platinum and ultrafiltrate platinum. Antitumor activity included two partial responses in metastatic melanoma and ovarian cancer, and an additional CA-125 normalization (from 133 IU/l) in a suspected ovarian cancer. AP5346 administered weekly for 3 weeks out of every four is tolerated up to a dose of 640 mg Pt/m2 on the first cycle when given with antiemetic prophylaxis. The pharmacokinetics of AP5346 indicates a prolonged half-life, and evidence of antitumor activity was observed at this dose level.

Pharmacokinetics and tissue distribution of platinum in rats following single and multiple oral doses of LA-12 [( OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)

The pharmacokinetics of total and free plasma platinum (Pt) and Pt tissue distribution were investigated in rats after oral administration of ( OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) (LA-12). Plasma and ultrafiltrate were sampled until 48 h and tissue samples were taken at 24 and 48 h after single doses of 38.6 or 540 mg LA-12/kg, and after once-a-day dosing of 4.3 or 38.6 mg kg −1 LA-12 over 14 consecutive days. Total plasma Pt concentrations increased less than proportionally to the 14-fold increase in the single dose. The mean C max values of 1.5 and 6.3 mg L −1 were observed at 0.5 and 1 h, respectively, and the mean AUC values achieved were 29 and 144 mg h L −1. The highest tissue Pt concentrations were found in the liver and kidneys. Platinum was undetectable in the brain while in other tissues (muscle, skin, heart, lungs), the concentrations were lower (after single dose) or similar (after multiple doses) when compared to the plasma C max values. Plasma Pt concentrations after once-a-day dosing of 38.6 mg kg −1 were two- to three-fold less than that after a single dose while Pt concentrations in various tissues rose two- to four-fold. Accumulation of Pt was even higher in the kidneys (seven-fold) and spleen (nine-fold). After once-a-day dosing, tissue Pt levels increased proportionally with the dose within the range from 4.3 to 38.6 mg kg −1. At the same time, the increase in total plasma Pt concentrations was 40% less than proportional. Concentrations of Pt in the plasma ultrafiltrate decreased rapidly with the initial half-life of 1 h.

Population pharmacokinetics of total and unbound plasma cisplatin in adult patients.

To investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. Pharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. Data from 43 patients were available for analysis. A linear two-compartment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h(-1) for clearance and 21.1 and 23.4 l for central distribution volume (V(1)). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V(1) was dependent on BSA. The elimination rate constant for plasma-bound platinum (modelled as metabolite formation) was 0.014 h(-1). The pharmacokinetic parameter, f(m)/V(m), a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m(2). The covariate modelling of CL, V(1) and f(m)/V(m) improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. The results support the conventional dose adjustment of cisplatin based on BSA. They also support the need for a dose reduction in case of renal insufficiency.

Pharmacokinetics of oxaliplatin during chronomodulated infusion in metastatic gastrointestinal cancer patients: A pilot investigation with preliminary results

Several clinical trials have demonstrated that the three-drug combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of 5-FU during chronomodulated infusion are available but up to now not for oxaliplatin. In this pilot study, the platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of oxaliplatin, 5-FU and LV in 7 patients with metastatic gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal drug delivery rate of: oxaliplatin (25 mg/m2/d, peak at 16:00 hours), 5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.

Determination of total platinum in plasma and plasma ultrafiltrate, from subjects dosed with the platinum-containing N-(2-hydroxypropyl)methacrylamide copolymer AP5280, by use of graphite-furnace Zeeman atomic-absorption spectrometry.

AP5280 is an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer to which are linked tetrapeptide side chains containing bioactive platinum complexes at their C-terminal sides. We have developed and validated a rapid and sensitive analytical assay for the determination of total platinum concentrations in plasma, and free platinum of an AP5280 origin in plasma ultrafiltrate (PUF), of subjects dosed with AP5280. The total platinum levels were determined by use of graphite-furnace atomic-absorption spectrometry (GF-AAS) with Zeeman correction after appropriate dilution of the plasma sample with plasma-hydrochloric acid 0.2 mol L(-1) (1:5) as diluent. The limit of quantitation of this assay is 0.25 micromol L(-1) platinum in plasma. Linear calibration curves were obtained over the concentration range 0.25-5.0 micromol L(-1). Accuracy was between 87.7% and 104.2% and precision was 15.3% at the lowest concentration and less than 14% for all other levels tested. Accuracy and precision were thus in accordance with generally accepted criteria for analytical methods. Analysis of samples obtained from patients receiving AP5280 demonstrated the applicability of the described assay. Analysis of free platinum in PUF was performed by use of a previously validated and reported assay from our institute in which the same instrumental method is used.

A preliminary pharmacokinetic study of docetaxel, carboplatin and concurrent radiotherapy for regionally advanced squamous cell carcinoma of the head and neck

This work investigates the pharmacokinetics and toxicity resulting from the concomitant use of low dose carboplatin (CBCA)/docetaxel (DTX) plus concurrent radiotherapy in patients with head and neck cancer. The study comprised 11 patients with stage III–IV head and neck cancer. All patients received 2 Gy radiotherapy daily, 5 fractions per week, up to a planned total of 70 Gy over 7 weeks. CBCA (AUC 0.4 mg/ml, min/day) was also administrated as 20 min i.v. infusion, starting 1 day before the first radiotherapy fraction. CBCA was administered for 5 consecutive days every 2 weeks (weeks 1, 3, 5 and 7). DTX 30 mg/m 2 (1 h i.v. infusion) was given as a single dose on days 10, 24 and 38. CBCA on day 1 and DTX on day 10 were analysed to determine the concentration–time curves during the first 24 h. CBCA C max and C min in 2–5 days and on day 15 and 29, as well as total plasma platinum on days 2, 3, 4, 5, 29 and 43 were also assayed. By calculating the non-compartmental pharmacokinetic parameters of the two drugs from the available plasma concentrations we found in the first week values similar to those reported in the literature as single agents. In contrast, during subsequent weeks (weeks 3 and 5), a significant and progressive increase of platinum levels was observed. So, it could be assumed that after 2 weeks of CBCA and DTX treatment a bias in dose calculation occurred because the linear relationship between creatinine clearance (used to calculate the expected AUC through the Calvert formula) and CBCA clearance was no longer observed.

Cisplatin Pharmacokinetics and Its Nephrotoxicity in Diabetic Rabbits

Background: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. Methods: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. Results: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. Conclusions: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.

Effects of a cisplatin-chondroitin sulfate A complex in reducing the nephrotoxicity of cisplatin.

To assess the effects of a macromolecular prodrug in reducing the nephrotoxicity of cisplatin (CDDP), chondroitin sulfate A (CSA) with a mean molecular weight of 23,000 Da was used to form a complex with CDDP, and the pharmacokinetics and toxicology of the resulting complex were examined in rats in comparison with those of CDDP. The total plasma platinum levels and urinary accumulation were determined up to 3 h following a bolus injection of 2 mg/kg. The results of the pharmacokinetic analysis showed that the complex suppressed the rapid distribution of CDDP, decreased the renal clearance and resulted in over fivefold higher AUC values within 3 h in comparison with CDDP treatment. In addition, the plasma levels of the drug following administration of the complex decreased greatly with time throughout the experimental period (3-24 h), whereas a slow elimination was observed following CDDP administration, which was due to the irreversible protein binding of CDDP. The tissue-to-plasma partition ratio at 10 min also indicated that the CDDP-CSA complex controlled the perfusion of CDDP to tissues, especially to the kidney. The accumulation in various tissues was evaluated at 3 h and 24 h following the injection of 5 mg/kg. Marked differences in renal accumulation were found within 3 h. Significant reductions in accumulation in the kidney, lung, muscle and whole blood were found within 24 h of administration of the complex. The renal toxicity of the CDDP-CSA complex was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (Cr) and the ratio of terminal kidney weight to body weight at doses of 2 mg/kg and 5 mg/kg. The complex displayed a much lower nephrotoxicity at 5 mg/kg in comparison to CDDP, and similar results were obtained at 2 mg/kg. This suggests that the complex changed the toxicodynamics of CDDP. Moreover, the anticancer activity of the CDDP-CSA complex, tested against SW 4800 human colon cancer cells and HeLa human cervix cancer cells in vitro, showed no decrease as compared with that of free CDDP. We conclude that the CDDP-CSA complex had the same activity as the parent drug but showed reduced nephrotoxicity at high doses of CDDP through an improvement in the pharmacokinetics of CDDP, which resulted from both the minimization of entry into normal tissues and renal clearance. In addition, it is also possible that different intracellular interactions in renal cells play a role in protection against the nephrotoxicity of high doses of CDDP.

An analysis of potential factors allowing an individual prediction of cisplatin-induced anaemia

Severe cisplatin (CP)-induced anaemia significantly impairs the patient's quality of life. Prevention based on erythropoietin (EPO) administration would be cost-effective providing that individual predictive factors of anaemia are identified. The aim of the present study was to identify parameters able to predict the occurrence of CP-related anaemia. This prospective study was conducted on 40 head and neck cancer patients receiving a CP (100 mg/m 2, intravenous (i.v.) on day 1) — 5-fluorouracil (5-FU, 1 g/m 2/d×5 days by continuous infusion) induction chemotherapy. Three cycles were given at 3-weekly intervals. Platinum pharmacokinetics (total and ultrafilterable plasma platinum concentration measured 16 h after CP administration) and 5-FU pharmacokinetics (full-cycle plasma area under the curve, (AUC 0–105h) were determined at the first cycle. Anaemia was defined as the haemoglobin (Hb) loss computed between pretreatment Hb and Hb concentration measured 1–2 days before third cycle administration. The median Hb loss was 22 g/l (mean 24±15, range 0–66). Significant loss of Hb (Hb loss >30 g/l) occurred in 15 patients (38%) and 3 of them also received a blood transfusion. Patient age, 5-FU AUC 0–105h and total platinum concentration were unrelated to Hb loss. In contrast, ultrafilterable (UF) platinum concentration was significantly correlated to Hb loss: the higher the UF platinum concentration, the greater the Hb loss ( P=0.015). A discriminant analysis allowed a cut-off value for UF platinum to be proposed to identify patients developing significant loss of Hb: 91% of patients exhibiting a UF platinum concentration above 50 ng/ml developed significant loss of Hb in contrast to 18% in the group of patients with a UF platinum concentration below 50 ng/ml (odds ratio (95% confidence interval, CI) of 46 (4.7–446)). In conclusion, the present platinum pharmacokinetic survey may be proposed as a valuable approach to identify patients at risk for developing severe anaemia.

Neoadjuvant Etoposide, Ifosfamide, and Cisplatin Followed by Concomitant Thoracic Radiotherapy and Continuous Cisplatin Infusion in Stage IIIb Non-small Cell Lung Cancer

To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.