Higher Area Under The Concentration-time Curve Research Articles

Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Background: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). Methods: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. Results: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 μg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1–2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. Conclusions: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.

Analyses of AUC(0-12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus.

The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0–12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0–12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0–12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of patients receiving only tacrolimus and for 25.0–31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1–5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0–12) exposure value. This indicates good compatibility of the dosage and the AUC(0–12) method. The Bland–Altman plot demonstrated that C0 and AUC(0–12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0–12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576–0.736), p < 0.01. Moreover, AUC(0–12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0–12) might influence the results.

Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma.

This study aimed to characterize the population pharmacokinetics and exposure‐response relationship of propranolol (Hemangiol® Syrup for Pediatric) in infants with infantile hemangioma. Using nonlinear mixed‐effects modeling with 63 pooled sets of plasma concentration‐time data from 32 Japanese patients aged 35‐150 days, we described the disposition of propranolol adequately by a 1‐compartment model with first‐order absorption. The estimated population mean apparent clearance and apparent central volume of distribution were 9.34 L/h and 146 L, respectively. Body weight and postnatal age influenced the population pharmacokinetic model. The clinical end points—success (complete or nearly complete resolution of the target hemangioma) and failure—at weeks 12 and 24 were characterized by logistic regression using the area under the concentration‐time curve (AUC), estimated from the final population pharmacokinetic model, as an exposure predictor. The logistic regression showed that a higher AUC was associated with a higher probability of successful treatment. At each exposure level, probability of successful treatment was correlated with gestational age and treatment duration. Model‐predicted probabilities of successful treatment were consistent with actual results in the clinical trial. Simulations using several dosing regimens indicated that oral propranolol at 3 mg/kg per day was effective and would be appropriate for treating Japanese infants. These simulation results can support optimization of dosing regimens, such as selecting amounts, treatment durations, and dosing intervals, for clinical use.

Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy.

ABSTRACTEach year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.

Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function

The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr) = 50-79 ml min(-1) ], moderate [CLcr = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]). Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort. Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.

Pharmacokinetics and tissue distribution study of tanshinone IIA after oral administration of Bushen Huoxue Qubi granules to rats with blood stasis syndrome.

Background:Bushen Huoxue Qubi (BHQ) granules, a traditional Chinese medicine preparation, has been clinically used for the treatment of the blood stasis syndrome.Objective:The main objective is to investigate whether the diseased condition would alter the pharmacokinetics and tissue distribution of tanshinone IIA in BHQ, which was given orally to the acute blood stasis rats.Materials and Methods:The main bioactive constituent in BHQ, tanshinone IIA, was measured in the plasma and tissues of animals by the high performance liquid chromatography with ultraviolet detection. The analysis was successfully performed on an Agilent TC-C18 column (250 × 4.6 mm I.D., 5 μm) protected with a Octadecylsilane (ODS) guard column (10 × 4.6 mm I.D., 5 μm). The mobile phase was aqueous solution (A) (containing 0.40% aqueous acetic acid) and acetonitrile (B). The conditions of the solvent gradient elution were 35-40% (B) in 0-15 min, 40-42% (B) in 15-18 min and 42-70% (B) in 18-30 min at a flow rate of 1.0 mL/min. Detection was conducted with wavelength of 270 nm at 30°C.Results:Good linearity relationships were found (r2> 0.9955) over the investigated concentration range for bio-samples. Blood stasis was associated with significantly higher area under the concentration-time curve (AUC), the maximum plasma concentration (Cmax) and biological half-life (t1/2), lower total body clearance (CL) and apparent volume of distribution (Vd) of tanshinone IIA in plasma and higher AUC0-t of tanshinone IIA in the analyzed tissues of rats treated with BHQ.Conclusion:Blood stasis could alter pharmacokinetics and tissue distribution of tanshinone IIA in BHQ.

Safety of PK-Guided IV Bu Cy VP-16 Preparative Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation for Lymphoma: Findings From a Multi-Center Phase II Study in North America

AbstractAbstract ▪813▪This icon denotes a clinically relevant abstract Background:Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods:Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (>24,000 mM*min or <16,000 mM*min), in which case the subsequent dosing was further adjusted. VP-16 (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. Transplant-related mortality (TRM), defined by death from any cause other than disease progression, was monitored throughout the trial. After median 2 years of follow-up, the outcomes will be compared with a BEAM regimen control group from the CIBMTR registry, using pre-specified matching criteria. Results:A total of 202 subjects with Hodgkin (n=65) and non-Hodgkin lymphoma (n=137) were enrolled from 32 centers in the US and Canada.196 subjects had both test PK and confirmatory PK results. Test PK demonstrated that 36.2% (n=71) of the patients had exposure outside of expected range (1,250 μM*min ± 20%): higher AUC (>1,500 μM*min) in five patients (2.6 %) and lower AUC (<1,000 μM*min) in 66 (33.7%). These would have been dosed outside the total target AUC range if dose was not individualized based on test PK. Mean Bu clearances were comparable between test and Day -8 PK, 3.04 ± 0.48 ml/min/kg and 3.03 ± 0.49 ml/min/kg, respectively. Accordingly, 94.9 % of patients (n=186) fell within the target range (AUC, 20,000 μM*min ± 20%), using consistent doses on Days -8 through -5. The other ten patients (5.1%) required dose alteration for the last two days of conditioning due to clearance changes between test PK and confirmatory PK (Day -8): a dose reduction in eight patients (4.1%) and a dose increase in two (1.0%).An early subset-analysis by age in June 2011 revealed that 4 of 18 subjects older than 65 years suffered TRM. Consequently, the protocol was amended to lower the inclusion age limit to 65. The final TRM at day 100 was 4/18 (22.2% [95%CI; 6.4–47.6%]) for patients older than 65 years and 5/184 (2.7% [95%CI; 0.9–6.2%]) for those 65 years old or younger. PK results indicated no extraordinary Bu exposure in TRM cases. The most frequently observed grade ≥ 3 adverse events (CTCAE ver. 3.0) were febrile neutropenia 55.1 % (Grade 3: 52.2%; Grade 4: 2.9%; no Grade 5), stomatitis 37.7% (all Grade 3 events) and nausea 9.7% (all Grade 3 events). No case of hepatic veno-occlusive disease (HVOD) meeting Baltimore criteria was reported. Conclusions:A pre-conditioning test dose estimated individual PK parameters and accurately predicted Day-8 PK in 95% of the subjects. This strategy personalized the dosing for optimal Bu exposure preventing the Bu overexposure or underexposure that would have occurred in over a third of patients. The toxicity of PK-guided IV BuCyVP-16 preparative regimen was low for patients younger than 66 years of age. This approach resulted in no incidence of HVOD. Disclosures:Costa:Otsuka: Research Funding. Off Label Use: Off label use of busulfan in non hodgkin and hodgkin lymphoma. Waller:Outsuka: Research Funding. Freytes:Otsuka Pharmaceuticals: Research Funding. Shea:Otsuka : Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka America Pharmaceuticals Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Vaughan:Pierre Fabre: Honoraria.

Pharmacokinetics and Safety of a Novel Conditioning Regimen, Individualized Once-Daily Intravenous Busulfan with Bortezomib, in Relapsed Multiple Myeloma Patients Undergoing a Second Autologous Hematopoietic Stem Cell Transplantation

Abstract 4509 BACKGROUND:Once multiple myeloma (MM) relapses after a first autologous hematopoietic stem cell transplantation (HSCT), long-term disease control is challenging because of limited therapeutic options. A second autologous HSCT is one of the options although the choice of conditioning regimens has not been thoroughly investigated. Past studies demonstrated that adding oral busulfan (Bu) to melphalan for conditioning regimen prior to a first HSCT resulted in better disease control of MM than melphalan single administration [Lahuerta et al, Haematologica. 2010;95:1913]. Nonetheless, the risk of hepatic veno-occlusive disease (VOD) hinders the use of oral Bu as a part of the conditioning regimen. Intravenous (IV) Bu eliminates the unpredictable bioavailability of the oral drug, whereas pharmacokinetic (PK)-directed dose optimization reduces inter-individual variability in the metabolism of Bu, resulting in decreased incidence of VOD and improvement in the control of hematologic malignancies [Andersson et al, Biol Blood Marrow Transplant 2002;8:477]. In addition, a proteasome inhibitor like bortezomib may have synergy with an alkylating agent for conditioning prior to HSCT in myeloma [Lonial et al, Clin Cancer Res 2010; 16: 5079], but the safety of a combination with Bu has not been investigated to date. Here we report results from a multicenter, prospective Phase 2 study to examine the pharmacokinetics of IV Bu and safety with bortezomib as a conditioning regimen for a second autologous HSCT. METHODS:30 patients with relapsed MM who had a first autologous HSCT ≥1 year prior to the planned HSCT were enrolled from eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between days 12 and 9 prior to HSCT. Serial blood samples were drawn up to 360 min after the start of the infusion. A central laboratory measured Bu concentrations, determined Bu exposure as area under the concentration-time curve (AUC) using WinNonlin software, and recommended individualized PK-directed dosing in order to achieve a total regimen AUC of 20,000 μM·min. Using the patient-specific PK-directed dose, IV Bu was administered over 3 hours once daily from Day -5 to Day -2. In all patients, a second PK analysis was conducted on Day -5 to confirm the PK-directed dose. Bu doses were adjusted on Day -3 and Day -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. RESULTS:All 30 patients who enrolled in this study had been treated with high dose melphalan before a first HSCT. The median time from the first to second HSCT was 31.4 months (range 12.0 – 119.2 months). Disease status prior to the second HSCT was VGPR (n=6), PR (n=12), SD (n=2), and PD (n=10). Test PK revealed that 40.0 % (n=12/30) of the patients had doses outside of target range (1,250 μM·min +/− 20%), based on expected exposure using a fixed dose of 0.8 mg/kg. Specifically, infusion of the test dose resulted in 1,500 μM·min or higher AUC in 3.3% (n=1/30) and 1,000 μM·min or lower AUC in 36.7% (n=11/30) of patients. In order to achieve the target AUC, daily PK-directed dose of IV Bu when conditioning started on Day -5 ranged between 1.99 mg/kg and 4.73 mg/kg: lower than 3.2 mg/kg in 12 subjects and higher than 3.2 mg/kg in the remaining 18. Confirmatory PK on Day -5 demonstrated that mean Bu clearances were comparable to that from test PK: 3.03 ml/min/kg for test dose and 2.93 ml/min/kg for Day - 5. Consequently, using a test dose followed by PK-directed Bu dosing, 93.3% of patients (n=28/30) fell within the target range (AUC, 20,000 μM·min +/−20%). Only two patients (6.7%) needed subsequent daily dose adjustment on Day -3 and Day -2. No instances of VOD, seizure, or worsening neuropathy have been reported to date. One death was reported by Day 30 after transplant in a patient with Parkinsonism who died of pulmonary complications. CONCLUSION:This multicenter, prospective study reveals that a pre-transplant test dose PK allows accurate targeting of busulfan dosing. The conditioning regimen of bortezomib and IV busulfan with PK-directed dose optimization is well tolerated in patients with relapsed MM who undergo second autologous HSCT. Disclosures:Freytes:Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfex and bortezomib as conditioning regimen for autologous transplant in patients with multiple myeloma. Yeh:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Shaughnessy:Otsuka: Consultancy, Honoraria, Speakers Bureau. White:Otsuka: Consultancy, Honoraria. Rodriguez:Millennium: Research Funding, Speakers Bureau; Otsuka: Research Funding. Yu:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka Pharmaceutical Development and Commercialization, Inc.: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Johnson & Johnson: Research Funding.

Pharmacokinetic targeting of i.v. BU with fludarabine as conditioning before hematopoietic cell transplant: the effect of first-dose area under the concentration time curve on transplant-related outcomes

We used pharmacokinetic (PK) targeting of BU in 145 consecutive patients treated with fludarabine and i.v. BU. BU was given once daily at 130 mg/m(2) per day on days 1 and 2; doses for days 3 and 4 were adjusted in 92 patients (63%) to an average daily area under the concentration-time curve (AUC) of 5300 μM/min. In the remaining 53 patients, the first-dose AUC was within the target range and no dosing adjustments were required. First-dose AUC, maximum concentration and clearance were not correlated with age, race, ethnicity, performance status, or hematopoietic cell transplant comorbidity index. Women had higher clearance than men (median 2.9 vs 2.5 mL/min/kg; P=0.001). BU toxicities were not associated with first-dose AUC or any other PK parameter measured. First-dose BU AUC was not associated with non-relapse mortality (NRM) or survival, but higher AUC was predictive of relapse. We did not find an increased risk of toxicity or NRM in patients with high first-dose AUC presumably because of the dose adjustment. We conclude that PK targeting of BU as described here provides a simple, safe and effective method of delivering high BU doses before transplantation in a wide variety of patients.

Pharmacokinetics of Bcl-2 antisense oligonucleotide (G3139) combined with doxorubicin in SCID mice bearing human breast cancer solid tumor xenografts

To evaluate the pharmacokinetic (PK) properties of Bcl-2 antisense oligodeoxynucleotide G3139 when combined with the anthracycline anticancer drug doxorubicin (DOX) in a model of MDA435/LCC6 human breast cancer in severely compromised immunodeficient (SCID) mice. An orthotopic model of MDA435/LCC6 solid breast tumors was developed by bilateral implantation of passaged cells in female SCID-RAG2 mice. The G3139 plasma profile was compared for two common routes of administration (i.v. or i.p.) in single and multiple dose treatment regimens of 5 mg/kg G3139 alone or with simultaneous DOX (5 mg/kg) administration. At selected times, plasma and major organs were assayed for [3H]G3139 using scintillation counting and DOX determined using HPLC. The molecular integrity of G3139 was analyzed using SDS-PAGE. The PKs of G3139 and DOX were evaluated using a two-compartment model. G3139 administered i.v. at 5 mg/kg revealed a biexponential plasma concentration-time curve with a Cmax of 99.9 microg/ml and elimination half-lives of 0.03 h and 9.8 h, respectively, which resulted in an area under the concentration-time curve (AUC) of 15.9 microg x h/ml. G3139 administered i.p. showed a plasma absorption, distribution and elimination profile typical of this route of administration, characterized by half-lives of 0.03 h, 0.2 h and 8.9 h, respectively and a Cmax of 8.6 microg/ml. Based on AUC comparisons, the bioavailability of G3139 injected i.p. was 84% compared to i.v. administration. Subtle changes were observed in G3139 PKs after three prior i.p. doses of G3139. Specifically, a six-fold slower absorption rate, lower Cmax (6.9 microg/ml), increased Tmax (0.2 h), and an AUC of 17.4 microg x h/ml were observed, consistent with concentrations approaching saturation levels in tissue sites to which G3139 distributes. Coadministration of DOX had significant effects on the PK properties of G3139, manifested by an increased Cmax (11.2 microg/ml), higher AUC (19.7 microg x h/ml), and ninefold lower plasma clearance for single-dose G3139 administration. G3139 in plasma remained largely intact (< 17% degraded in plasma over 4 h), and increased plasma protein association occurred as a function of time. G3139 was detected in both healthy and tumor tissue after i.v. and i.p. administration. The highest tissue levels of G3139 were observed in the kidneys (40 microg/g), and low levels (< 2 microg/g) were detected in lung, heart and muscle. The rate of accumulation of G3139 in organs was dependent upon G3139 levels in plasma and the presence of coadministered DOX. Significant accumulation of G3139 was observed in solid tumors, with peak levels of approximately 5 microg G3139/g tumor, and approximately a two-to threefold tumor/muscle AUC ratio. The kinetics of G3139 accumulation in tumor tissue increased with increasing circulating G3139 concentration. The tissue distribution properties of DOX were also altered in the presence of coadministered G3139: in the presence of G3139, tumor exposure to DOX increased two-to threefold without alteration in plasma DOX PKs. These findings indicate that drug-drug interactions between G3139 and DOX are modest and favorable in that elevated tumor DOX levels are achieved without compromising G3139 tumor uptake or significantly altering plasma drug concentrations.

Clinical Pharmacokinetics and Dose Optimisation of Carboplatin

Carboplatin shares some of the therapeutic advantages of cisplatin, but without a significant incidence of the dose-limiting neurotoxicity and nephrotoxicity which is experienced with cisplatin. However, its use is associated with dose-limiting bone marrow suppression. Carboplatin is present in the blood as 3 distinct species. These are total platinum and 2 unbound species, carboplatin itself and a decarboxylated platinum-containing degradation product. The 2 main methods used to assay the unbound species are flameless atomic absorption spectrophotometry and high performance liquid chromatography. The first of these methods assays both unbound platinum species, the second is specific for carboplatin. Both unbound species have similar pharmacokinetic profiles for the first 12 hours post-dose. Carboplatin appears to have a linear pharmacokinetic profile over the doses used clinically and does not interact significantly with drugs that are used commonly in combination chemotherapy. The pharmacokinetics of carboplatin are adequately described by an open 2-compartment model with elimination from the central compartment. Its clearance is proportional to the glomerular filtration rate and the volume of distribution of the central compartment appears to correlate with extracellular fluid volume. The elimination half-life varies with renal function and is typically between 2 and 6 hours in patients with a normal glomerular filtration rate and may be as long as 18 hours in patients with impaired renal function. Relationships between systemic exposure to carboplatin, described as the area under the concentration-time curve (AUC), and both toxicity and response have been described. For toxicity the strongest evidence exists for a relationship between AUC and thrombocytopenia. To a lesser extent the relationship between AUC and neutropenia has also been described. Patients already treated with platinum analogues have been shown to develop a greater degree of myelosuppression from any given AUC. In addition, some evidence suggests a relationship between the shape of the concentration-time curve and myelotoxicity, where constant infusions appear less likely to cause myelosuppression on a mg/m2 dose administration basis. The relationship between AUC and response rate is not as clear, this may be related to the lack of studies describing both the dose and AUC of carboplatin. There appears to be a more clearly defined AUC-response relationship for ovarian cancer than for other malignancies, with an AUC of between 5 and 7 mg/ml.min being associated with the maximal response rate [located at the plateau on an AUC-response curve]. However, new data suggest that higher AUCs may lead to greater response rates. Data from testicular cancer also strongly supports an AUC-response relationship with an increased number of treatment failures with carboplatin AUCs < 5 to 6 mg/ml.min. Given the AUC-effect relationships described above a number of studies have been performed to develop models to describe the relationship between both dose and AUC and dose and platelet nadir. In adults, perhaps the most common method is that of Calvert which describes the relationship between dose and AUC. Paediatric formulas have also been described. More recently a number of limited sampling strategies have been proposed as well as Bayesian dose individualisation techniques.