Population pharmacokinetics of lenalidomide in multiple myeloma patients

Guglieri-López, Beatriz; Pérez-Pitarch, Alejandro; Moes, Dirk Jan A R; Porta-Oltra, Begoña; Climente‐Martí, Mónica; Guchelaar, Henk‐Jan; Merino-Sanjuán, Matilde

doi:10.1007/s00280-016-3228-y

Cited by 15 publications

(25 citation statements)

References 29 publications

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“…A population PK model, previously developed using data from daratumumab monotherapy studies [ 14 ], was used to fit concentration–time data from the four combination studies. No direct impact of the background therapies on the PK of daratumumab was expected given the lack of overlapping clearance mechanisms for daratumumab and the co-administered small-molecule therapies [ 22 – 24 ]. NONMEM ® 7.2 software (ICON, Dublin, Ireland) was used for population PK modeling.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Dimopoulos

Sonneveld

et al. 2018

Adv Ther

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IntroductionDaratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.MethodsFour clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.ResultsPharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.ConclusionThese data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.FundingJanssen Research & Development.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0815-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Dimopoulos

Sonneveld

et al. 2018

Adv Ther

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“…In a recent population‐pharmacokinetic study, it was shown that lenalidomide exposure was dependent not only on the renal function but also on the body‐surface area (BSA). The authors suggested that BSA should be taken into account in the dosing adjustment in advance to prevent toxicity.…”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma

Morival

Oumari

Lenglet

et al. 2017

Hematological Oncology

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Treatment of myeloma is a long-term treatment mainly based on all-oral combinations of drugs. Because oral drugs have a more complex pharmacokinetics compared with IV treatments, an appropriate knowledge of the factors that may alter their systemic exposure is of particular clinical relevance. Both drug-drug interactions, food-effect, and dose-adaptation in renal and hepatic impairment may influence the systemic drug levels with a potential impact on drug efficacy or safety. Moreover, a better control of drug exposure may improve the side effect profiles of these treatments with a favourable impact on patient compliance. Furthermore, as long-term treatments, these drugs may also alter the systemic exposure of coadministered medications in these rather old patients. The aim of this review was to identify the factors modifying the systemic exposure of oral drugs used in myeloma by focusing on the pharmacokinetic drug-drug interactions and the effects of renal and hepatic impairment and of food impact.

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“…In this preliminary analysis, creatinine clearance (CrCl), a marker of renal function, was the only significant covariate of lenalidomide apparent clearance, and no differences in PK were observed among MM, MCL, and MDS patients . Recently, the PopPK of lenalidomide was explored in a small number of subjects (n = 15) who had multiple myeloma; in this study, the authors found that both creatinine clearance and body surface were covariates that impacted lenalidomide's pharmacokinetics …”

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confidence: 99%

“…19 Recently, the PopPK of lenalidomide was explored in a small number of subjects (n = 15) who had multiple myeloma; in this study, the authors found that both creatinine clearance and body surface were covariates that impacted lenalidomide's pharmacokinetics. 20 However, PK differences appeared to exist between HVs and patients for oral immunomodulatory drugs. Plasma exposure (AUC) to lenalidomide has been shown to be higher in patients than in HVs, even when renal function was comparable.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

Connarn¹,

Hwang²,

Gao³

et al. 2017

Clinical Pharm in Drug Dev

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A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs.

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Population pharmacokinetics of lenalidomide in multiple myeloma patients

Cited by 15 publications

References 29 publications

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

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