Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen, Nianhang; Zhou, Simon; Palmisano, Maria

doi:10.1007/s40262-016-0432-1

Cited by 73 publications

(69 citation statements)

References 61 publications

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“…These molecules have similar molecular structures; however, their often subtle chemical differences alter not only their substrate specificities but also their PK profiles. For example, lenalidomide is not subject to significant CYP‐based or conjugative metabolism and is instead eliminated mostly through renal excretion of the unchanged drug; in contrast, pomalidomide is primarily metabolized by CYP1A2 and CYP3A, with a low fraction excreted in urine as unchanged drug . Pomalidomide exposures when administered with the CYP3A inhibitor ketoconazole were 118.8% and 107.3%, for AUC and C max , respectively, of that when administered alone .…”

Section: Discussionmentioning

confidence: 99%

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Ogasawara¹,

MacGorman²,

Liu³

et al. 2019

The Journal of Clinical Pharma

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Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.

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Section: Discussionmentioning

confidence: 99%

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Ogasawara¹,

MacGorman²,

Liu³

et al. 2019

The Journal of Clinical Pharma

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“…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 . Interestingly, PopPK analysis for pomalidomide, a similar oral immunomodulatory drug, suggested that peripheral distribution of pomalidomide was greater in MM patients than in HVs …”

mentioning

confidence: 99%

“…Plasma exposure (AUC) to lenalidomide has been shown to be higher in patients than in HVs, even when renal function was comparable. 21 Interestingly, PopPK analysis for pomalidomide, a similar oral immunomodulatory drug, suggested that peripheral distribution of pomalidomide was greater in MM patients than in HVs. 22 The current analysis aimed to develop a PopPK model to quantitatively describe the PK disposition of lenalidomide and to investigate whether disease or other intrinsic factors alter the disposition of lenalidomide.…”

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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“…Lenalidomide is excreted by the kidney, and the drug-metabolizing enzyme cytochrome P450 (CYP) is not involved in this metabolizing process (7,8). Lenalidomide is known to be a poor substrate of P-glycoprotein (P-gp), but no clinically significant drug interactions between lenalidomide and P-gp substrates and inhibitors have been observed (9).…”

Section: Introductionmentioning

confidence: 99%

Combination of lenalidomide and low-dose dexamethasone therapy promotes the anticoagulant activity of warfarin in patients with immunoglobulin light-chain amyloidosis

et al. 2017

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Abstract. The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1.7-fold during treatment. The median time to reach maximum values was 17 days. Horn's drug Interaction Probability Scale indicated a possible interaction between lenalidomide and warfarin. These patients exhibited no marked alterations in hepatic function or serum albumin concentrations prior to and following combination chemotherapy and no additional administration of CYP2C9 inhibitors or vitamin K supplements was conducted. In addition, no patient experienced chemotherapy-induced nausea or appetite loss. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Therefore, the combination of warfarin and lenalidomide may cause a pharmacodynamic interaction, more likely by inhibiting the production of interleukin-6. In conclusion, clinically important interactions between warfarin and lenalidomide and low-dose dexamethasone therapy were observed in AL amyloidosis patients, where INR values signi ficantly increased. Therefore, close and regular monitoring of patients during the course of treatment is important, and the dose of warfarin should be reduced if required.

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Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Cited by 73 publications

References 61 publications

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

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

Combination of lenalidomide and low-dose dexamethasone therapy promotes the anticoagulant activity of warfarin in patients with immunoglobulin light-chain amyloidosis

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