CYP2C19 phenotype and body-weight-guided voriconazole initial dose in infants and children after hematopoietic cell transplantation

Background : Prophylactic voriconazole use is recommended in children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential due to its narrow therapeutic index. Known covariates do not sufficiently explain large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. Objectives : We investigated genetic and clinical covariate association with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. Methods : This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. Results : We analyzed plasma voriconazole and n-oxide metabolite concentrations from 58 children aged <21 years (n=12 in age <2 years). A two-compartment parent mixed linear/nonlinear model best described our data. CYP2C19 phenotype and body weight were significant covariates (both p<0.05). Our model performance in age <2 years was comparable to other age groups. Simulation of the final model suggested the following dosages to attain target steady-state trough concentrations of 1.5 - 5.0 mg/L in CYP2C19 normal phenotype: 16 mg/kg (weight <15 kg), 12 mg/kg (weight 15-30 kg), 10 mg/kg (weight >30 kg), whereas dosages were 33-50% lower for CYP2C19 poor/intermediate and 25-50% higher for CYP2C19 rapid/ultrarapid phenotypes. Conclusions : We propose a new starting dosage regimen, combined with therapeutic drug monitoring for intravenous voriconazole in children of all ages. Future studies should validate this dosing regimen.

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Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2015.09.005 ◽

2015 ◽

Vol 21 (11) ◽

pp. 1883-1887 ◽

Cited By ~ 22

Author(s):

H. Joachim Deeg ◽

Christopher Bredeson ◽

Stephanie Farnia ◽

Karen Ballen ◽

Vikas Gupta ◽

...

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Age Groups ◽

Hematopoietic Cell ◽

Curative Therapy

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Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes

Blood Advances ◽

10.1182/bloodadvances.2018029421 ◽

2019 ◽

Vol 3 (14) ◽

pp. 2179-2187 ◽

Cited By ~ 8

Author(s):

J. B. Langenhorst ◽

C. van Kesteren ◽

E. M. van Maarseveen ◽

T. P. C. Dorlo ◽

S. Nierkens ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Failure ◽

Hematopoietic Cell Transplantation ◽

Strong Predictor ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Conditioning Regimens

Abstract Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area–based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day −9/−12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P < .001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P < .001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and “renal function” or “therapeutic drug monitoring,” to achieve optimal fludarabine exposure might improve survival.

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Impact of Pharmacogenetics and Therapeutic Drug Monitoring On Optimizing Voriconazole Dosing in Pediatric Patients Undergoing Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2012.11.162 ◽

2013 ◽

Vol 19 (2) ◽

pp. S176-S177

Author(s):

Ashley Teusink ◽

Alexander Vinks ◽

Kejian Zhang ◽

Stella Davies ◽

Lisa Filipovich ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Cell Transplantation ◽

Drug Monitoring ◽

Pediatric Patients ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Therapeutic Drug

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The impact of pre-transplant body weight on short- and long-term outcomes after allogeneic hematopoietic cell transplantation in adults using different weight classification tools

Bone Marrow Transplantation ◽

10.1038/bmt.2015.219 ◽

2015 ◽

Vol 51 (1) ◽

pp. 144-147 ◽

Cited By ~ 2

Author(s):

P Urbain ◽

G Ihorst ◽

J Finke ◽

H Bertz

Keyword(s):

Body Weight ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Long Term Outcomes ◽

Short And Long Term ◽

The Impact ◽

Weight Classification

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Influence of Glutathione S-Transferase (GST) Gene Polymorphisms On the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.1179.1179 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1179-1179

Author(s):

Sung-Doo Kim ◽

Je-Hwan Lee ◽

Seong-Gil Ryu ◽

Eun-Hye Hur ◽

Mun Jung Kang ◽

...

Keyword(s):

Body Weight ◽

Gene Polymorphism ◽

Actual Body ◽

Cell Transplantation ◽

Gene Polymorphisms ◽

Hematopoietic Cell Transplantation ◽

Regression Coefficient ◽

Hematopoietic Cell ◽

Adult Patients ◽

Actual Body Weight

Abstract Abstract 1179 Poster Board I-201 Introduction: Intravenous (iv) busulfan can yield a more consistent dosing and pharmacokinetic profile than oral formulation, but there is still inter-patient variability in systemic exposure with iv busulfan. GST gene polymorphisms may explain the variability because busulfan is metabolized in liver through conjugation with GST family. Thus, we investigated the influence of polymorphisms of 3 GST genes, GSTA1, GSTM1, and GSTT1 on the clearance of iv busulfan in adult patients undergoing hematopoietic cell transplantation (HCT). Patients and Methods: We analyzed the PK data from 60 patients, who were included in a randomized trial of 4-times-daily (0.8 mg/kg q 6 h) versus once-daily (3.2 mg/kg once a day) iv busulfan in a conditioning therapy for HCT (Biol Blood Marrow Transplant 2007;13:1095). Limited sampling strategy was used for PK studies, which were performed for the first busulfan dosing using a validated LC with tandem MS. Busulfan plasma clearance (CL) was derived from 1 compartment model. GSTA1 was genotyped by PCR followed by RFLP, and GSTM1- and GSTT1-null genotypes were identified by PCR procedure. Results: GSTA1 genotyping revealed GSTA1*A/*A in 46 patients (77%) and GSTA1*A/*B in 14 (23%). GSTM1-null genotype was found in 25 patients (43%) and GSTT1-null genotype in 34 (59%). Each polymorphism of GST genes was not associated with sex or age of the patients. In univariate analysis, clearance (CL, mL/min/kg) of iv busulfan was significantly associated with GSTA1 polymorphisms (*A/*A vs. *A/*B, 2.036 ± 0.340 vs. 1.789 ± 0.295, P=0.017), but not with GSTM1 (present vs. null, 2.012 ± 0.390 vs. 1.915 ± 0.279, P=0.274) or GSTT1 (present vs. null, 2.047 ± 0.286 vs. 1.917 ± 0.380, P=0.064) polymorphisms. Actual body weight in kilogram was also significantly associated with CL of iv busulfan (Pearson's correlation coefficient, -0.420; P=0.001). Linear regression analysis demonstrated that GSTA1 gene polymorphism (regression coefficient, -0.255; 95% CI, -0.440 to -0.071; P=0.008) and actual body weight (regression coefficient, -0.012; 95% CI, -0.091 to -0.005; P=0.001) were independently significant factors for CL of iv busulfan. Null genotype of GSTM1 and/or GSTT1, although each polymorphism was not a significant factor, showed decreased clearance of iv busulfan both in patients with GSTA1 *A/*A and those with GSTA1 *A/*B (Figure 1). The CL was similar between in patients with GSTA1 *A/*A with null genotype of both GSTM1 and GSTT1 and in those with GSTA1 *A/*B with present genotype of both GSTM1 and GSTT1. Conclusion: GSTA1 gene polymorphism was an important determining factor for the clearance of iv busulfan. Polymorphisms of GSTM1 and GSTT1 genes also appeared to have a supplementary role in the pharmacokinetics of iv busulfan. Disclosures: No relevant conflicts of interest to declare.

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Comparison of two mycophenolate mofetil dosing regimens after hematopoietic cell transplantation

Bone Marrow Transplantation ◽

10.1038/bmt.2008.428 ◽

2009 ◽

Vol 44 (2) ◽

pp. 113-120 ◽

Cited By ~ 23

Author(s):

P Jacobson ◽

S F El-Massah ◽

J Rogosheske ◽

A Kerr ◽

J Long-Boyle ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Dosing Regimens

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Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01426-20 ◽

2020 ◽

Vol 64 (12) ◽

Author(s):

S. Abdalla ◽

C. Briand ◽

M. Oualha ◽

M. Bendavid ◽

A. Béranger ◽

...

Keyword(s):

Body Weight ◽

Pediatric Population ◽

Compartment Model ◽

Therapeutic Drug ◽

Oral Acyclovir ◽

Mixed Effect ◽

Varicella Zoster ◽

Dosing Regimens ◽

Trough Concentrations ◽

Simplex Virus

ABSTRACT Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m2) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m2). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.)

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