Role Of Therapeutic Drug Monitoring Research Articles

A Pilot Study to Evaluate the Role of Therapeutic Drug Monitoring of Pegfilgrastim in Lymphoma Patients Receiving Chemotherapy

Background: Despite primary prophylaxis of febrile neutropenia (FN) with pegfilgrastim, studies have demonstrated a significant number of breakthrough FN events among Asian lymphoma patients receiving chemotherapy. This study was designed to investigate the association of pegfilgrastim concentrations during the lowest point of absolute neutrophil count (ANC nadir) after chemotherapy administration and the occurrence of breakthrough FN, to evaluate whether Therapeutic drug monitoring of pegfilgrastim can guide management of FN. Methods: This was a single-centre, prospective cohort study of Asian lymphoma patients who received prophylactic pegfilgrastim after completion of their chemotherapy. Pegfilgrastim serum concentrations were measured from blood samples taken during ANC nadir and at development of breakthrough FN using an enzyme-linked immunosorbent assay. Descriptive statistics, t-tests and correlation curves were used in the statistical analyses. Results: Nineteen patients were recruited from May to August 2012 and received 21 cycles of pegfilgrastim. Three (15.8%) developed breakthrough FN. The median pegfilgrastim concentration among patients who developed breakthrough FN was 0.257 (0.231–0.631) ng/ml, compared to 0.299 (0.001–0.829) ng/ml in patients who did not (p=0.740). Baseline ANC levels were significantly lower in patients with breakthrough FN (3.59 × 109/L, range 2.71–3.87) versus those who did not (5.36 × 109/L, range 2.80–16.48; p=0.014). Conclusion: There was no difference in pegfilgrastim levels during ANC nadir between patients who developed breakthrough FN and those who did not, but the study was underpowered. Therapeutic drug monitoring of pegfilgrastim cannot be recommended at this time.

Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing

Voriconazole exhibits highly variable, non-linear pharmacokinetics and is associated with a narrow therapeutic range. This study aimed to investigate the population pharmacokinetics of voriconazole in adults, including the effect of CYP2C19 genotype and drug-drug interactions. Non-linear mixed effects modelling (NONMEM) was undertaken of six voriconazole studies in healthy volunteers and patients. Dosing simulations to examine influential covariate effects and voriconazole target attainment (2-5 mg/L) stratified by CYP2C19 phenotype were performed. We analysed 3352 voriconazole concentration measurements from 240 participants. A two-compartment pharmacokinetic model with first-order oral absorption with lag time and Michaelis-Menten elimination best described voriconazole pharmacokinetics. Participants with one or more CYP2C19 loss-of-function (LoF) alleles had a 41.2% lower Vmax for voriconazole. Co-administration of phenytoin or rifampicin, St John's wort or glucocorticoids significantly increased voriconazole elimination. Among patients receiving 200 mg of voriconazole twice daily, predicted trough concentrations on day 7 were <2 mg/L for oral and intravenous regimens for 72% and 63% of patients without CYP2C19 LoF alleles, respectively, with 49% and 35% below this threshold with 300 mg twice daily dosing. Conversely, these regimens resulted in 29%, 39%, 57% and 77% of patients with CYP2C19 LoF alleles with voriconazole trough concentrations ≥5 mg/L. Current dosing regimens for voriconazole result in subtherapeutic exposure in many patients without CYP2C19 LoF alleles, suggesting the need for higher doses, whereas these regimens result in supratherapeutic exposure in a high proportion of patients with reduced CYP2C19 activity. These findings support the essential role of therapeutic drug monitoring in ensuring efficacious and safe voriconazole exposure.

Interactions between valproic acid and quetiapine/olanzapine in the treatment of bipolar disorder and the role of therapeutic drug monitoring

The anticonvulsant valproic acid and the atypical antipsychotics olanzapine and quetiapine provide synergistic mood-stabilising, antidepressant and antipsychotic activities in the treatment of bipolar and schizoaffective disorders. Existing literature shows that pharmacokinetic and pharmacodynamics drug-drug interactions (DDIs) possibly occur with the use of such a combination. Clinical reports of a possible interaction between the drugs leading to an increased risk of adverse drug reactions have also emerged. The main objective of this paper is to review the incidence of DDIs between the anticonvulsant and the antipsychotics, to postulate the possible mechanisms of the interaction and to establish whether certain target populations are at an increased susceptibility to such interactions. The usefulness of therapeutic drug monitoring (TDM) of the antipsychotics to monitor for an interaction was also assessed. A systematic database search was carried out using the search engine provided by PubMed using the following key words: olanzapine, quetiapine, valproic acid, pharmacokinetic drug-drug interaction, bipolar disorder, therapeutic drug monitoring. Evidence of a possible clinically relevant DDI between valproic acid and both antipsychotics has been uncovered. A possible mechanism for the interactions has been postulated, and the importance of TDM has been discussed. Further research is required to determine whether DDIs occur with the concurrent use of valproic acid and olanzapine or quetiapine, and to investigate the potential of TDM as a clinical tool in improving pharmacotherapy and preventing toxicity.

What is Needed for Optimal Therapeutic Drug Monitoring?

BioanalysisVol. 6, No. 2 EditorialWhat is needed for optimal therapeutic drug monitoring?William ClarkeWilliam ClarkeDepartment of Pathology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Sheikh Zayed Tower B-1020F, Baltimore, MD 21287, USA. Search for more papers by this authorEmail the corresponding author at wclarke@jhmi.eduPublished Online:14 Jan 2014https://doi.org/10.4155/bio.13.314AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: harmonizationlaboratory improvementpersonalized medicineproficiency testingquality assurance–QCtherapeutic drug monitoringReferences1 Pippenger CE, Gillen HW. Gas chromatographic analysis for anticonvulsant drugs in biologic fluids. Clin. Chem.15(7),582–590 (1969).Crossref, Medline, CAS, Google Scholar2 Feldman RG, Pippenger CE. The relation of anticonvulsant drug levels to complete seizure control. J. Clin. Pharmacol.16(1),51–59 (1976).Crossref, Medline, CAS, Google Scholar3 Kupferberg HJ. Quantitative estimation of diphenylhydantoin, primidone and phenobarbital in plasma by gas-liquid chromatography. Clin. Chim. Acta29(2),282–288 (1970).Crossref, Medline, CAS, Google Scholar4 Kupferberg HJ, Longacre-Shaw J. Mephobarbital and phenobarbital plasma concentrations in epileptic patients treated with mephobarbital. Ther. Drug Monit.1(1),117–122 (1979).Crossref, Medline, CAS, Google Scholar5 Levy G. What are narrow therapeutic index drugs? Clin. Pharmacol. Ther.63(5),501–505 (1998).Crossref, Medline, CAS, Google Scholar6 Oette M, Kroidl A, Gobels K et al. Predictors of short-term success of antiretroviral therapy in HIV infection. J. Antimicrob. Chemother.58(1),147–153 (2006).Crossref, Medline, CAS, Google Scholar7 Teng JF, Mabasa VH, Ensom, MH. The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. Ther. Drug Monit.34(1),85–97 (2012).Crossref, Medline, CAS, Google Scholar8 Bach DM, Straseski JA, Clarke W. Therapeutic drug monitoring in cancer chemotherapy. Bioanalysis2(5),863–879 (2010).Link, CAS, Google Scholar9 Horowitz GL. Establishment and use of reference values. In: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th Edition). Burtis CA, Ashwood ER, Bruns, DE (Eds). Elsevier Saunders, St. Louis, MO, USA, 95–118 (2012).Google ScholarFiguresReferencesRelatedDetails Vol. 6, No. 2 Follow us on social media for the latest updates Metrics Downloaded 184 times History Published online 14 January 2014 Published in print January 2014 Information© Future Science LtdKeywordsharmonizationlaboratory improvementpersonalized medicineproficiency testingquality assurance–QCtherapeutic drug monitoringFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Therapeutic drug monitoring with valproate–Why product selection is an important factor

There is a modest collection of literature describing the pharmacokinetic and clinical differences between the extended-release form of divalproex sodium (Depakote ER®) and the delayed-release form (Depakote®). Published articles are quick to espouse the extended-release formulation, especially in the setting of seizure control. Reasons commonly cited include a longer dosing interval, improved patient compliance, a more consistent pharmacokinetic profile, and fewer side effects. There are fewer articles discussing these differences in the context of treating mental illnesses, namely bipolar affective disorder. This article aims to compare these two formulations of divalproex with a special focus on their pharmacokinetic profiles, uses in psychiatric illness, and the role of therapeutic drug monitoring. The patient case that follows will describe a scenario in which a patient was prescribed each formulation during an acute hospitalization.

Are lopinavir and efavirenz serum concentrations in HIV-infected children in the therapeutic range in clinical practice?

Background:In antiretroviral treatment the role of therapeutic drug monitoring via measurement of serum levels remains unclear, especially in children.Aim:To quantify exposure to LPV and EFV in children receiving therapy in a routine clinical setting in order to identify risk factors associated with inadequate drug exposure.Method:A prospective study was conducted in a routine clinical setting in Tygerberg Children's Hospital, South Africa. A total of 53 random serum levels were analyzed. Serum concentrations were determined by an established high-performance liquid chromatography method.Results:Of 53 HIV-infected children treated with lopinavir (n = 29, median age 1·83 y) or efavirenz (n = 24, median age 9·3 years), 12 showed serum levels outside the therapeutic range (efavirenz) or below Cmin (lopinavir). Low bodyweight, rifampicin co-treatment, and significant comorbidity were potential risk factors for inadequate drug exposure.Conclusion:These findings, together with previous studies, indicate that therapeutic drug monitoring can improve the management of antiretroviral therapy in children at risk.

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Introduction: Fondaparinux is contraindicated in patients with severe renal impairment and renal failure due to an increased risk of bleeding. Dosing recommendations in this high-risk patient population, including the role of therapeutic drug monitoring using anti-Xa levels, are lacking. Methods: A retrospective chart review was conducted from October 1, 2006 to November 30, 2012. Subjects were identified based on ICD-9 procedure and diagnosis codes for renal insufficiency and RRT. Patients included were at least 18 years old, received prophylactic fondaparinux for 72 hours, received ≥ 1 dose in an intensive care unit, and had a CrCl < 30 mL/min or RRT during therapy. Subjects included were divided into 3 cohorts: CrCl < 30 mL/min without RRT, hemodialysis (HD), or continuous veno-venous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and VTE. Patients were screened for bleeding and VTE events using ICD-9 codes and validated via chart review. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. The prophylactic fondaparinux anti-Xa range is 0.39-0.5 mcg/mL per our laboratory assay. Results: Thirty-one patients with severe renal impairment were included. Ten (32.3%) patients had a CrCl < 30 mL/min, 16 (51.6%) required CVVH, and 5 (16.1%) HD. The median defined daily dose in the CrCl < 30 mL/min without RRT, HD, and CVVH cohorts was 2.5 mg, 0.9 mg, and 1.9 mg, respectively. Anti-Xa monitoring occurred in 15 (48.4%) patients, most in the CVVH cohort (67%). Only 61% of anti-Xa levels were obtained 3-5 hours post dose. Median anti-Xa serum concentrations in the CrCl < 30 mL/min without RRT, HD, and CVVH cohorts were 0.2, 0.4, and 0.4 mcg/mL. Two (6.5%) patients experienced clinically significant bleeds. Both were receiving RRT and neither underwent anti-Xa monitoring. No patients experienced a VTE post fondaparinux initiation. Conclusions: Optimal fondaparinux dose and dosing frequency in patients with severe renal impairment is unknown and practice is variable. Anti-Xa monitoring may be beneficial to guide therapy in high-risk populations. Additional data is needed to recommend fondaparinux dosing strategies in critically ill patients with severe renal impairment.

Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus

Nuclear factor of activated T cells (NFAT) is a family of transcription factors involved in regulating the immune response. The canonical NFAT pathway is calcium-dependent and upon activation, NFAT is dephosphorylated by the phosphatase, calcineurin. This results in its translocation from the cytoplasm to the nucleus and transcription of downstream target genes that include the cytokines IL-2, IL-10, and IFNγ. Calcineurin inhibitors including tacrolimus inhibit the NFAT pathway and are used as immunosuppressants in transplant settings to prevent graft rejection. There is, as yet, no direct means to monitor tacrolimus pharmacodynamics. In this study, a rapid, quantitative, image cytometry-based measurement of nuclear translocation of NFAT1 is used to evaluate NFAT activation in T cells and its tacrolimus-induced inhibition. A strong dose-dependent correlation between NFAT1 inhibition and tacrolimus dose is demonstrated in vitro. Time kinetic analysis of NFAT1 inhibition in plasma from stable renal transplant recipients before and after an in vivo dose with tacrolimus correlated with the expected pharmacokinetic profile of tacrolimus. This was further corroborated by analysis of patients' autologous CD4 and CD8 T cells. This is the first report to show that the measurement of NFAT1 activation potential by nuclear translocation can be used as a direct, sensitive, reproducible and quantitative pharmacodynamic readout for tacrolimus action. These results, and the rapid turnaround time for this assay, warrant its evaluation in a larger clinical setting to assess its role in therapeutic drug monitoring of calcineurin inhibitors.

The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea

To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

Report From the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation, London, 7–10 April 2013

Antifungal prophylaxis reduces the risks of invasive fungal infection (IFI), all-cause mortality and fungal-related mortality in highly immunosuppressed haemato-oncology patients, but questions remain about the role of therapeutic drug monitoring in this patient population. There is also continuing debate concerning the benefits and risks of empirical versus pre-emptive antifungal therapy when breakthrough IFI occurs during prophylaxis. These topics were discussed during the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation, held in London in April 2013.

PHC-020 Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil (5-FU) in Gastrointestinal Cancer Patients

BackgroundAppropriate dosing of chemotherapeutic drugs is critical to reducing mortality and increasing progression-free survival. 5-fluorouracil (5-FU) is a widely used chemotherapeutic drug in gastrointestinal cancer. The standard approach to dosing...

Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events

BackgroundVoriconazole is approved for treatment of invasive aspergillosis and other invasive fungal infections, but the role for therapeutic drug monitoring (TDM) is not clear.MethodsWe performed a retrospective cohort study of patients at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center from 2007–2009. We compared the effect of therapeutic levels on clinical outcomes and evaluated the relationship between drug levels and adverse events.ResultsA total of 108 patients had voriconazole TDM performed, of whom 84 (77.8%) had a hematologic malignancy and 47 (43.5%) had undergone hematopoietic stem cell transplantation. The primary reasons for treatment were presumed pulmonary aspergillosis (n = 83, 76.8%), other invasive mould infections (n = 13, 12.0%) and candidiasis (n = 9, 8.3%). There was a high degree of variability in voriconazole drug levels among patients (r2 = 0.01; range, <0.10 - 20 mg/L). Of the 46 patients with proven or probable invasive fungal disease, 25 (54.3%) achieved partial or complete response to therapy. There was no significant relationship between therapeutic drug levels and achievement of complete or partial response at 12 weeks (OR 0.29, 95% CI: 0.05-1.34) or radiologic response (OR 1.46, 95% CI: 0.32-7.83). Overall, 45 (41.7%) patients experienced adverse events. Voriconazole levels > 5.5 mg/L were not associated with increased incidence of encephalopathy (OR 3.08, 95% CI 0.79-11.0) or hepatotoxicity (OR 2.45, 95% CI 0.49-10.1).ConclusionsVoriconazole therapeutic drug levels were not associated with improvement in clinical outcomes among patients with proven or probable invasive fungal disease. We also did not find an association between supratherapeutic drug levels and hepatoxicity or encephalopathy. It is possible that the utility of voriconazole therapeutic drug monitoring to improve clinical efficacy or decrease adverse events may be limited to a subset of high-risk patients.

Clinical review: Tuberculosis on the intensive care unit

Rates of tuberculosis (TB) are increasing in most west European nations. Patients with TB can be admitted to an ICU for a variety of reasons, including respiratory failure, multiorgan failure and decreased consciousness associated with central nervous system disease. TB is a treatable disease but the mortality for patients admitted with TB to an ICU remains high. Management challenges exist in establishing a prompt diagnosis and administering effective treatment on the ICU with potentially poor gastric absorption and high rates of organ dysfunction and drug toxicity. In this review reasons for ICU admission, methods of achieving a confident diagnosis through direct and inferred methods, anti-tuberculosis treatment (including steroid and other adjuvant therapies) and specific management problems with particular relevance to the intensivist are discussed. The role of therapeutic drug monitoring, judicious use of alternative regimes in the context of toxicity or organ dysfunction and when to suspect paradoxical tuberculosis reactions are also covered. Diagnostic and therapeutic algorithms are proposed to guide ICU doctors in the management of this sometimes complicated disease.

The role of therapeutic drug monitoring in the treatment of cytomegalovirus disease in kidney transplantation

Cytomegalovirus (CMV) infection is a common complication following solid organ transplantation that may severely affect the outcome of transplantation. Ganciclovir (GCV) and its prodrug valganciclovir are successfully used to prevent and treat CMV infection; however, in a small percentage of patients, CMV gene mutations may lead to drug resistance. GCV resistance is defined as increasing CMV viremia or progressive clinical disease during prolonged antiviral therapy, due to CMV gene mutation. This has emerged as a new challenge, especially because alternative drugs such as cidofovir and foscarnet have a number of important side effects. Here we report the case of a kidney transplanted patient who experienced life-threatening CMV disease, which initially appeared to be GCV-resistant, but was instead found to be associated with inadequate antiviral drug levels. The patient was then successfully treated by monitoring plasma GCV levels. We suggest using plasma GCV monitoring in the management of all cases of critical CMV disease, in which GCV resistance is suspected.

Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib

A simple HPLC method has been developed to measure imatinib and N-desmethylimatinib (norimatinib) in plasma or serum at concentrations attained during therapy. Adaptation of this method to LC-MS/MS also allows dasatinib assay. A small sample volume (100 μL HPLC-UV, 50 μL LC-MS/MS) is required and analysis time is <5 min in each case. Detection was by UV (270 nm) or selective reaction monitoring (two transitions per analyte) tandem mass spectrometry. Assay calibration was linear (0.05-10 mg/L imatinib, 0.01-2.0 mg/L norimatinib and 1-200 µg/L dasatinib), with acceptable accuracy (86-114%) and precision (<14% RSD) for both methods. A comparison between whole blood and plasma confirmed that plasma is the preferred sample for imatinib and norimatinib assay. For dasatinib, although whole blood concentrations were slightly higher, plasma is still the preferred sample. Despite considerable variation in the (median, range) plasma imatinib and norimatinib concentrations in patient samples [1.66 (0.02-4.96) and 0.32 (0.01-0.99) mg/L, respectively, N = 104], plasma imatinib was >1 mg/L (suggested target for response) in all but one sample from patients achieving complete molecular response. As to dasatinib, the median (range) plasma dasatinib concentration was 13 (2-143) µg/L (N = 33). More observations are needed to properly assess the potential role of therapeutic drug monitoring in guiding treatment with dasatinib.

Selective Serotonin Reuptake Inhibitors (SSRIs): Therapeutic Drug Monitoring and Pharmacological Interactions

New-generation antidepressants are a heterogeneous class of drugs used in the treatment of depression and related disorders. This review deals with the first new-generation antidepressant class to enter the pharmaceutical market, i.e., selective serotonin reuptake inhibitors (SSRIs), which are still the most prescribed and widely used ones. Their common characteristics are the comparable clinical efficacy, good tolerability and relative safety in comparison to "first generation antidepressants", i.e. classic tricyclic antidepressants and monoamine oxidase inhibitors. This class of drugs includes fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine and, since 2011, vilazodone. In this review, the main pharmacodynamic and pharmacokinetic properties of the six commercially available SSRIs are described, focusing on side and toxic effects, chemical-clinical correlations, interactions with other drugs, the role of therapeutic drug monitoring (TDM) and related bioanalytical methodologies.

Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

Background and aimsTherapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235pmol/8×108 erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level. MethodsHundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity. ResultsForty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263pmol/8×108 erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235pmol/8×108 erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04). ConclusionsThiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response

Population Pharmacokinetic (PK) Modeling of Hydroxyurea for Therapeutic Drug Monitoring Applications in Children and Adolescents with Sickle Cell Disease

Abstract 2136 Introduction:Sickle cell anemia (SCA) is an inherited disorder of abnormal hemoglobin synthesis. Hydroxyurea (HU) is the only disease modifying agent available for use in patients with SCA. Clinically, HU has been shown to decrease pain, number of transfusions, and development of acute chest syndrome as well as improve life expectancy in adults with SCA. Although HU is increasingly utilized to treat children with SCA, drug exposure-response relationships and therapeutic drug monitoring are not well characterized in the pediatric population. The exposure-response relationships of HU are currently being evaluated as is the potential role of therapeutic drug monitoring. Objective:The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe HU disposition in serum and urine following oral drug administration in pediatric patients. Such a model is required for exploring concentration-effect relationships in children with SCA taking HU. Methods:PK was determined in 20 subjects (mean age 10.5 yr, range 5–17 yr) with SCA either as a single dose (SD, n=6, average dose 17.4 mg/kg) or at steady state (SS, n=14, average daily dose 25.5 mg/kg). Blood and urine samples for HU assay were taken throughout the 24 hour period post HU administration. HU was quantitated by a validated gas chromatography–mass spectrometry (GC-MS) method. Population nonlinear mixed-effect modeling was done using NONMEM software. Measured HU concentrations at specific sampling time points were compared to model predicted area under the curves (AUCs) to find the most predictive relationship. Results:A one-compartment model with first-order absorption and two elimination pathways (metabolic and renal) was used. The mean absorption rate constant differed for children < 8.5 years of age (19.5 h−1) as compared to those ≥ 8.5 years of age (2.1 h−1) and demonstrated high intersubject variability (76%). The population apparent volume of distribution (V/F) was 21.3 L (for an average weight patient of 30.7 kg) with an intersubject variability of 24.7%. The apparent renal (CLu/F) and metabolic (CLm/F) clearance was 3.47 L/hr and 3.52 L/hr, respectively, with the same between subject variability of 42%. Significant relationships (p<0.005) between both CL/F and V/F and body weight were found with these parameters increasing by 2.96% and 2.49%, respectively, for every kilogram difference from the median weight. Significant linear correlations were apparent between the plasma HU concentration at 0.75, 1, 1.5, 2, 4, and 6 hours post-dose; the most significant (p<0.01, r2 =0.71) occurring at 1.5 hours. Conclusion:In children with SCA, a population PK model parameterized from a classical PK study of HU was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 or 2 hours after an oral dose of the drug were especially predictive of systemic drug exposure (as reflected by AUC). Data from this study also suggest that there may be age related differences in absorption rates. Further studies are warranted to confirm this finding. Disclosures:Off Label Use: Hydroxyurea is not labeled for use in children.

Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide). The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

Mycophenolic Acid Pharmacokinetics During Maintenance Immunosuppression in African American and Caucasian Renal Transplant Recipients

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12-hour steady-state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.