Interpatient Variability In Drug Exposure Research Articles

An improved method for cytochrome p450 reaction phenotyping using a sequential qualitative-then-quantitative approach.

Cytochrome P450 reaction phenotyping to determine the fraction of metabolism values (fm) for individual enzymes is a standard study in the evaluation of a new drug. However, there are technical challenges in these studies caused by shortcomings in the selectivity of P450 inhibitors and unreliable scaling procedures for recombinant P450 (rCYP) data. In this investigation, a two-step "qualitative-then-quantitative" approach to P450 reaction phenotyping is described. In the first step, each rCYP is tested qualitatively for potential to generate metabolites. In the second step, selective inhibitors for the P450s identified in step1 are tested for their effects on metabolism using full inhibition curves. Forty-eight drugs were evaluated in step 1 and there were no examples of missing an enzyme important to in vivo clearance. Five drugs (escitalopram, fluvastatin, pioglitazone, propranolol, and risperidone) were selected for full phenotyping in step2 to determine fm values, with findings compared to fm values estimated from single inhibitor concentration data and rCYP with intersystem-extrapolation-factor corrections. The two-step approach yielded fm values for major drug clearing enzymes that are close to those estimated from clinical data: escitalopram and CYP2C19 (0.42 vs 0.36-0.82), fluvastatin and CYP2C9 (0.76 vs 0.76), pioglitazone and CYP2C8 (0.72 vs 0.73), propranolol and CYP2D6 (0.68 vs 0.37-0.56) and risperidone and CYP2D6 (0.60 vs 0.66-0.88). Reaction phenotyping data generated in this fashion should offer better input to physiologically-based pharmacokinetic models for prediction of DDI and impact of genetic polymorphisms on drug clearance. The qualitative-then-quantitative approach is proposed as a replacement to standard reaction phenotyping strategies. Significance Statement P450 reaction phenotyping is important for projecting drug-drug interactions and interpatient variability in drug exposure. However, currently recommended practices can frequently fail to provide reliable estimates of the fractional contributions of specific P450 enzymes (fm) to drug clearance. In this report, we describe a two-step qualitative-then-quantitative reaction phenotyping approach that yields more accurate estimates of fm.

Post-thrombolytic coagulopathy and complications in patients with pulmonary embolism treated with fixed-dose systemic alteplase

Alteplase treatment can cause a systemic coagulopathy although the incidence and contributory factors are unknown in pulmonary embolism (PE). Fixed-dosing of alteplase for PE may lead to interpatient variability in drug exposure and influence post-thrombolytic coagulopathy (PTC). While changes in fibrinogen and INR have been used to describe PTC, no universal PTC definition is available. Evaluate the incidence of PTC after alteplase treatment for PE, the effect of patient weight and blood/plasma volume and the association with bleeding complications. We conducted a retrospective cohort study of patients treated with alteplase for massive or high-risk submassive PE. Demographics, alteplase dosing, laboratory assessment of coagulopathy, and bleeding events were collected. The primary endpoint was incidence of PTC defined as an international normalized ratio (INR) > 1.5 or fibrinogen < 170mg/dL. Secondary outcomes included correlation between coagulopathies and alteplase dose normalized to actual body weight (ABW), ideal body weight (IBW), plasma volume (PV), and estimated blood volume (EBV). Bleeding events in patients with and without PTC were compared. 125 patients met criteria for inclusion in the study. PTC occurred in 35.3% of patients, with INR >1.5 in 21.8% and fibrinogen <170mg/dL in 26%. Alteplase dose >50mg was associated with increased odds of PTC (OR 6.5, CI 2.1-19.9). Dose normalized to ABW and EBV correlated weakly with absolute increase in post-alteplase INR (r =0.20, p =0.06 and r =0.21, p =0.057 respectively) and to percent change in INR (r =0.20, p = 0.058 and r =0.21, p =0.048 respectively). Dose/ABW, dose/PV, and dose/EBV each correlated moderately with absolute decrease in fibrinogen (r =-0.53, -0.49, and -0.47 respectively, p <0.001 for each) and percent change in fibrinogen (r = -0.55, -0.49, and -0.49 respectively, p < 0.001 for each). Dose/IBW correlated weakly with absolute and percent decrease in fibrinogen (r = -0.32, p =0.013 and r =-0.33, p =0.011). Patients with bleeding were more likely to have PTC (58.3% vs. 28.6%, p= 0.05) and a bleeding event was predictive of PTC (OR 5.33, 1.32-23.99). PTC is prevalent in patients with PE. PTC is influenced by alteplase dose and exposure parameters (ABW, IBW, PV, EBV) and may contribute to the bleeding risk.

Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps.

Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic associations are frequently used in children, and therefore pharmacogenomics-guided precision medicine is readily applicable to the pediatric population. Although heritable genetics are considered immutable, the impact of genetic variation in pharmacogenes is modified by other factors such as age-dependent changes in gene expression. Early evidence has emerged indicating that the interaction between ontogeny and pharmacogenomics determines whether or how genetics-based dosing algorithms should be adjusted in children versus adults. However, there is still a paucity of data describing pharmacogenomic associations in patient populations across the life span. Future research is much needed to evaluate the impact of pharmacogenomics on drug dosing specific to the pediatric population, along with consideration of other developmental and physiological factors uniquely related to drug disposition in this population.

Abstract 5048: Residual concentrations of cetuximab predict clinical response in head and neck cancer patients

Abstract Cetuximab administration is contingent upon the upfront determination of Ras mutational status, because mutated patients are unlikely to respond to this therapy. In addition to tumor genomics, drug exposure levels could be a critical yet largely underestimated issue, because several reports have already demonstrated that cetuximab pharmacokinetic parameters (i.e., clearance values) could be associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a highly simplified sample preparation procedure to assay cetuximab in patients while meeting the requirements of standard therapeutic drug monitoring in routine clinical practice. We used this method prospectively to evaluate the inter-patient variability in drug exposure, and to search whether those exposure levels could be associated with clinical endpoints. A total of 25 adult patients (22 M, 3F, mean age: 69 years) hospitalized for head and neck cancer and scheduled for a cetuximab-containing regimen (250 mg/m² QW) were included to perform this pilot study. Seven patients received concomitant radiotherapy and 14 patients received concomitant chemotherapy. 28% of patients displayed severe toxicities (CTC grading). Following RECIST assessment, 10 out of 25 patients (40%) had progressive disease and 60% were categorized as patients with clinical benefit (stable disease: 5 patients (20%), partial response: 7 patients (28%), complete response: 3 patients (12%)). A large inter-patient variability was observed among individuals. Mean cetuximab residual concentrations were 40.3 ± 20.3 µg/ml (CV: 51%, range 0-74.6 µg/ml) and mean cetuximab maximal concentrations were 126.9 ± 39.6 µg/ml (CV: 31%, range 65.1-210.6 µg/ml). No statistical difference was observed in cetuximab residual concentrations between patients with and without severe toxicities (36.7 ± 21.2 µg/ml VS. 41.8 ± 20 µg/ml, p&amp;gt;0.05, t test), nor in maximal cetuximab concentrations (117.1 ± 31.3 µg/ml VS. 130.3 ± 39.70 µg/ml, p&amp;gt;0.05, t test). Conversely, when comparing exposure levels in patients with clinical benefit to non-responding patients, a statistical difference was found in both cetuximab residual concentrations (49 ± 16.3 µg/ml VS. 25.8 ± 17 µg/ml, p&amp;lt;0.01, t test) and to a lesser extent in cetuximab maximal concentrations (143.7 ± 37.9 µg/ml VS. 100.9 ± 24.6 µg/ml, p&amp;lt;0.05, t test). Further ROC analysis showed that 33.8 µg/ml was the Cmin level associated with a probability of clinical benefit with 86% of sensitivity and 75% of specificity. These results advocate for the development of mass spec-based therapeutic drug monitoring of cetuximab in head and neck cancer patients. In addition to tumor molecular biology, drug exposure could be indeed a valuable actionable item to improve efficacy of cetuximab at bedside. Citation Format: Joseph Ciccolini, François Becher, Diane-Charlotte Imbs, Claire Fournel, Florence Duffaud, Bruno Lacarelle, Sebastien Salas. Residual concentrations of cetuximab predict clinical response in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5048. doi:10.1158/1538-7445.AM2017-5048

Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide.

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug–drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure–response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug–drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug–drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.

Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study.

Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure. Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks. During the first period, all patients received 800 mg of pazopanib once daily to reach steady-state exposure. During the second period, the patients either received a PK-guided individualized pazopanib dose or the registered fixed 800-mg dose. During the third period, these 2 dosing regimens were switched. The interpatient variability in pazopanib AUC0-24h during fixed dosing (27.3 coefficient of variation) was not significantly different when compared with the variability in AUC0-24h during PK-guided dosing (24.8 coefficient of variation). The percentage of patients within the target window during PK-guided dosing (53.9%) was not significantly different from the percentage during fixed dosing (46.2%). Both Ctrough and C24 were significantly (P < 0.001) correlated to pazopanib AUC0-24h (R = 0.596 and R = 0.940, respectively). Pazopanib AUC0-24h decreased 17% over time. PK-guided dosing did not reduce the interpatient variability in pazopanib exposure. In this study, the intrapatient variability in pazopanib exposure was relatively large compared with interpatient variability. This makes it challenging to achieve a target exposure within a predefined window. The causes of intrapatient variability must first be better understood and controlled, before PK-guided dosing can reduce the interpatient variability.

Predictive Value of CYP3A and ABCB1 Phenotyping Probes for the Pharmacokinetics of Sunitinib: the ClearSun Study

The wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib. A correlation analysis was performed between sunitinib pharmacokinetics and 1'OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile ((99m)Tc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate. In 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4 ng/mL at day 1 of a cycle to 88.1 ng/mL in the fourth week of treatment. A trend for a correlation was observed between (99m)Tc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1'OH-midazolam/midazolam ratio and sunitinib clearance (P = 0.008) and day 1 N-desethylsunitinib trough concentrations (P = 0.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4 L/h; P = 0.025). Phenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure-toxicity relationship.

Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer

Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30-40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4-activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined. Thirteen patients treated with sunitinib in a 4 weeks "on"-2 weeks "off" regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined. A significant correlation between midazolam exposure (AUC(0-7h)) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC(0-24h)) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter-patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C trough was highly correlated (r(2) = 0.94) with sunitinib AUC(0-24h). Sunitinib decreased midazolam exposure with 24 % (p = 0.034). Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation.

CYP3A4 phenotyping with midazolam to predict sunitinib exposure.

2592 Background: Patients treated with sunitinib show high inter-patient variability in drug exposure (40-60%), which is largely unexplained. Since sunitinib is metabolized by CYP3A4, variability in the activity of this enzyme may explain a considerable proportion of the observed variability. We therefore prospectively studied the relationship between CYP3A4 activity and systemic exposure to sunitinib. Methods: In fifteen patients treated with sunitinib in a four weeks “on” – two weeks “off” regimen the pharmacokinetics of sunitinib and its active metabolite SU12662 were assessed. To determine sunitinib+SU12662 steady-state exposure, samples were collected over 24hrs after at least 14 days of sunitinib therapy. To assess CYP3A4 activity, midazolam 7.5mg orally was administered on the final day of the two weeks “off”. Plasma concentrations were measured over a period of 7hrs to determine midazolam exposure. Exposures (AUC) were calculated using a trapezoidal approach (Phoenix WinNonlin v6.3). The relationship between CYP3A4 activity (midazolam exposure) and sunitinib+SU12662 exposure was determined by linear regression analysis. The percentage of variability in sunitinib+SU12662 exposure that could be explained by CYP3A4 activity was calculated by Pearson’s correlation. In addition, the correlation between sunitinib+SU12662 Ctrough levels and sunitinib+SU12662 exposure was assessed. Results: A strong correlation between midazolam exposure (AUC0-7hr) and steady-state sunitinib+SU12662 exposure (AUC0-24hr) was found (p= 0.002); CYP3A4 activity explained 55% of the observed inter-patient PK variability of sunitinib+SU12662. Furthermore sunitinib+SU12662 Ctrough levels were highly predictive (96%) for overall sunitinib+SU12662 exposure (AUC0-24hr). Conclusions: Midazolam as a phenotyping probe could be useful before start of sunitinib therapy to identify patients at risk for under- respectively overtreatment at a standard dosage regimen. Therefore, CYP3A4 phenotyping could be useful to individualize sunitinib therapy. Additionally, sunitinib+SU12662 trough levels are highly predictive for sunitinib+SU12662 exposure and thus can be used for monitoring and guiding sunitinib therapy in clinical practice. Clinical trial information: NCT01743300.

Long-term Follow-up of Stable Kidney Transplant Recipients After Conversion From Tacrolimus Twice Daily Immediate Release to Tacrolimus Once-daily Prolonged Release: A Large Single-Center Experience

BackgroundAdult kidney transplant recipients maintained on tacrolimus twice-daily (Tac BD) were given the opportunity to convert to tacrolimus once daily (Tac QD). Conversion was based upon a 1:1 mg:mg total daily dose ratio. MethodsBetween November 2007 and September 2010, 589 patients were converted at a mean post-transplant period of 4.6 years. We retrospectively reviewed routine clinical records to assess the safety of conversion to Tac QD for up to 12 months post-conversion. ResultsTac QD mean dose barely changed from preconversion values. Mean exposure (tacrolimus trough blood level [Cmin]) remained within the target window but was reduced by 12% (P = NS) with a trend toward less interpatient variability. Renal function at 12 months remained stable within 2.5% of the preconversion mean value. There were 14 (2.4%) cases of biopsy-proven acute rejection: 6 (1.0%) borderline and 8 (1.4%) Banff grade ≥ IA. Actuarial first year post-conversion graft survival was 96.3% and patient survival 99.0%. Twenty-eight patients (4.8%) discontinued Tac QD and were switched to sirolimus: 19 for malignancy, 6 for thrombotic microangiopathy, and 3 with severe vascular changes; 3 patients were reconverted to Tac BD. ConclusionsConversion from Tac BD to Tac QD in renal recipients was accompanied by stable renal function, a low risk of acute rejection, and less interpatient variability in drug exposure.

Practical guidelines for dose individualization of anticancer targeted drugs

For drugs such as anticancer agents every effort should be made to minimize inter-patient variability in drug exposure in order to maximize the benefit while maintaining an acceptable risk level of serious adverse effects. Anticancer drugs generally have a preferential route of elimination, either in urine or in bile and feces. In consequence, dose individualization to renal and liver function permits excessive toxicity to be avoided and expected therapeutic benefit to be achieved. However, less is known about the most appropriate starting doses of antineoplastic agents in these individuals. In this review, we discuss trials that have specifically assessed new targeted agents dosing strategies (mainly monoclonal antibodies and tyrosine kinase inhibitors) in the setting of overt biochemical renal and liver dysfunction and we proportionate recommendations and practical guidelines for dose individualization.

1678P - Predictive Value of Two Phenotyping Probes for the Pharmacokinetics of Sunitinib in Cancer Patients

ABSTRACT Background Cancer patients treated with sunitinib show a wide inter-patient variability in drug exposure. This may at least partly explain the variation in toxicity and efficacy related to sunitinib treatment. The primary aim of this study was to investigate whether the clearance of 2 phenotyping probes are related to the pharmacokinetics (PK) of sunitinib. Patients and methods A prospective multi-center study was performed in cancer patients treated with single agent sunitinib. PK of sunitinib and its active metabolite N-desethyl-sunitinib were measured at start of sunitinib intake and within 4 weeks of continuous daily dosing. A correlation analysis was performed between these PK data and midazolam clearance (as a CYP3A phenotyping probe) and hepatic 99mTc-MIBI scans (as a probe for ABCB1 [P-glycoprotein] activity). Results A total of 52 GIST and renal cell cancer patients were included in this study, of whom 46 were evaluable for analysis of sunitinib PK. Mean trough level of sunitinib, adjusted for dose, at day 1 of a new course was 14.7 ng/mL (range 7.2-28.9 ng/mL), and 56.2 ng/mL (range 19.1-151.1 ng/mL) in the 4th week of a treatment cycle. A significant correlation between N-desethyl-sunitinib trough levels and plasma clearance of midazolam (r = 0.58, P = 0.006) within 24 hours after the first intake of sunitinib was found. In addition, a trend was seen for the correlation between midazolam clearance and sunitinib trough levels at steady state (r = 0.26, P = 0.09). No correlation between sunitinib trough levels and hepatic 99mTc-MIBI clearance was seen in an interim analysis after 27 patients. Conclusions These observations show a correlation between the midazolam clearance test that serves as a probe for CYP3A and the exposure to sunitinib. Meanwhile, a lack of correlation was seen between sunitinib PK and the studied ABCB1 probe. These data could ultimately lead to a further personalization of sunitinib dosing. Additional investigations are in progress, including population PK modeling of sunitinib, and incorporation of pharmacogenetic parameters to further unravel the mechanisms behind these findings. Disclosure All authors have declared no conflicts of interest.

Abstract 1295: Relationship between pharmacokinetic (PK) sampling schema and reported PK variability of liposomes in patients

Abstract Introduction: Liposomal formulations offer advantages over small molecules including increased solubility, selective targeting potential and prolonged drug exposure. Compared with conventional formulations, these agents often have greater PK and pharmacodynamic variability, which is attributed to the role of the mononuclear phagocyte system in the clearance of liposomes. Inter-patient variability in drug exposure, represented by area under the curve (AUC), of encapsulated drug can be 20- to 100-fold. However, some nanoparticle and liposomal agents report lower inter-patient PK variability. Study design and sampling schema may affect the documentation of PK variability, due to the prolonged systemic exposure of encapsulated drug. Thus, we evaluated the reported PK variability of PEGylated CKD-602 (S-CKD602) and non-liposomal CKD-602 (NL-CKD-602) using a short (0-24 h) and long (0-336 h) sampling schema. Methods: S-CKD602 and NL-CKD-602 were administered at doses ranging from 0.5 to 2.1 mg/m2 in phase I studies of patients with advanced solid tumors. Blood samples were obtained from baseline to 336 h for S-CKD602 and from baseline to 24 h for NL-CKD-602. Plasma concentration of total (lactone + hydroxy acid) encapsulated CKD-602 from S-CKD602 and total CKD-602 from NL-CKD-602 were measured by LC-MS/MS. AUC from 0 to 24 h (AUC0-24) and 0 to 336 h (AUC0-336) were calculated. The coefficient of variance % (CV%) in AUC0-24 and AUC0-336 at each dose level were calculated for S-CKD602 and NL-CKD-602. Results: Conclusion: The inter-patient variability of exposure of S-CKD602 is 2.5- to 3.4-fold greater than that of NL- CKD-602. Current PK study designs limited to 24 h underestimate the inter-patient variability of exposure of S-CKD602. PK study design of liposomal agents requires an extended PK sampling schema to accurately describe its PK disposition. A limited sampling strategy that may be applied for all nanoparticles is under development to address this issue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2011-1295

Pharmacogenetic factors predicting the need for a higher dose of imatinib.

3098 Background: In patients treated with imatinib (Gleevec) a 4-fold interpatient variability in drug exposure exists, possibly as a result of pharmacogenetic (PG) variability which implicates tha...

Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors

Summary Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. Methods Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC(0–12), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. Results No association between dose normalized AUC(0–12) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. Conclusions Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib.

Antifungal serum concentration monitoring: an update

Invasive fungal infections (IFIs) are occurring with increasing incidence and are associated with significant morbidity and mortality. Understanding the relationship between the pharmacokinetic and pharmacodynamic properties of antifungals is essential to optimize the potential for favourable clinical and microbiological outcomes while minimizing risks of treatment-related toxicity. Antifungal serum concentrations may aid in the determination of appropriate dosing in select circumstances. The polyene and echinocandin classes of antifungals lack sufficient data to justify serum concentration monitoring in routine clinical practice. In contrast, serum concentration monitoring of flucytosine may help to reduce the risk of treatment-related haematological toxicity. Determination of itraconazole serum concentrations is advised in situations where the drug is used for prolonged periods to treat serious IFIs (such as invasive aspergillosis or histoplasmosis) because of variability in absorption following oral administration (most notable for the capsule formulation). The use of serum concentration monitoring during therapy with the extended-spectrum triazoles (i.e. voriconazole and posaconazole) is still evolving, due primarily to inter-patient variability in drug exposure combined with sparse data regarding relationships with efficacy (posaconazole) and both safety and efficacy (voriconazole).

Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body Surface Area Values

The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average +/- 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population. In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value < or = 1.65 m2 was 16% slower (P < .001), while an 18% faster clearance (P < .001) was observed in patients with a BSA value > or = 2.05 m2. CONCLUSION Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (< or = 1.65 m2; 1.66 m2 to 2.04 m2; > or = 2.05 m2) are recommended.

Monte Carlo Simulation in the Evaluation of Susceptibility Breakpoints: Predicting the Future: Insights from the Society of Infectious Diseases Pharmacists

Appropriate treatment with antimicrobials involves factors we cannot control. Factors such as interpatient variability in drug exposure, the minimum inhibitory concentration (MIC) of the infecting pathogen, and the patient's clinical status clearly affect the therapeutic response. Despite these uncertainties, we can estimate the probability of attaining a successful therapeutic outcome in the context of factors that are within our control. Chief among these are drug, dose, and the dosing interval. One way to predict the probability of a positive therapeutic outcome is through the use of an integrated pharmacokinetic-pharmacodynamic stochastic model. Pharmacokinetic-pharmacodynamic target attainment analyses using Monte Carlo simulation to integrate interpatient variability in drug exposure, drug potency, and in vivo exposure targets predictive of positive therapeutic outcomes are influencing antibacterial susceptibility breakpoints at home and abroad. The consequences of this paradigm shift are far reaching, affecting the commercial concerns of drug and susceptibility testing device manufacturers, perceptions about antimicrobial resistance, and ultimately patient care decisions.

New Approaches to Drug Development in Pediatric Oncology

This article reviews the changing paradigm of new drug development for childhood cancer. Although there have been dramatic improvements in the treatment and outcome for childhood cancer over the past 50 years, in some cancers, only limited progress has been made. New strategies to improve the outcome for poor-prognosis tumors and to minimize the long-term sequelae associated with therapy are required. Such strategies include a new pediatric-specific initiative for the preclinical testing of anticancer drugs for childhood malignancies, and ongoing research into the molecular heterogeneity of childhood tumors to facilitate the evaluation of molecularly targeted drugs. In addition, continued investigation into the genetic basis underlying interpatient variability in drug exposure and response is a priority. The goal of these initiatives is to improve the overall outcome for childhood cancer while minimizing the short and long-term sequelae associated with current treatment strategies.

The Bioavailability of Oral Methotrexate in Children with Inflammatory Bowel Disease

Methotrexate is used to treat patients with inflammatory bowel disease. Although no available pharmacologic data support the assumption that the bioavailability of methotrexate is diminished in patients with inflammatory bowel disease, most such patients receive methotrexate parenterally. The oral bioavailability of methotrexate was determined in 11 pediatric patients being treated with methotrexate for inflammatory bowel disease. Serial plasma methotrexate concentrations were determined after equal subcutaneous and oral doses of methotrexate. The mean bioavailability of methotrexate in patients with inflammatory bowel disease was 84% +/- 38%. Interpatient variability in drug exposure was similar after oral and subcutaneous administration. The bioavailability of methotrexate in patients with inflammatory bowel disease is no different from that observed in other disease states. Subcutaneous administration of methotrexate does not appear to decrease the interpatient variability in drug exposure. There is no sound pharmacologic basis for favoring administration of methotrexate via the subcutaneous route for patients with inflammatory bowel disease.