Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

Xu, Xu Steven; Ryan, Charles J.; Stuyckens, Kim; Smith, Matthew R.; Saad, Fred; Griffin, Thomas W.; Park, Youn C.; Yu, Margaret K.; Porre, Peter De; Vermeulen, An; Poggesi, Italo; Nandy, Partha

doi:10.1007/s40262-016-0425-0

Cited by 18 publications

(18 citation statements)

References 30 publications

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“…Abiraterone shows large between‐patient variability (40.7–140.0%) (EMA, ). Finally, a relation between drug exposure ( C trough ) and prostate‐specific antigen decrease and a relation between prostate‐specific antigen decrease and survival was shown for abiraterone, which indirectly points out the relevance of adequate exposure levels for optimal treatment outcome (Xu et al, ). A better understanding of abiraterone pharmacokinetics will help to optimize the dose of the individual patient.…”

Section: Introductionmentioning

confidence: 96%

Analytical challenges in quantifying abiraterone with LC–MS/MS in human plasma

Benoist

Meulen

Lubberman

et al. 2017

Biomedical Chromatography

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A method was developed and validated to quantify abiraterone in human plasma. During assay development several analytical challenges were encountered: limited stability in patient samples, adsorption to glass, co-elution with metabolites, and carry-over issues. Limited stability (2h) was found for abiraterone in fresh plasma as well as whole blood at ambient temperature. When kept at 2–8°C, abiraterone in plasma was stable for 24h and in whole blood for 8h. Adsorption of abiraterone to glass materials was addressed by using polypropylene throughout the method. Carry-over was reduced to acceptable limits by incorporating a third mobile phase into the gradient. The chromatographic separation of abiraterone with its multiple metabolites was addressed by using a longer analytical column and adjusting the gradient. Abiraterone was extracted by protein precipitation, separated on a C18-column with gradient elution and analyzed with tandem quadrupole mass spectrometry in positive ion mode. A stable deuterated isotope was used as the internal standard. The assay ranges from 1–500 ng/mL. Within–and between day precisions and accuracies were below 13.4% and within 95–102%. This bioanalytical-method was successfully validated and applied to determine plasma concentrations of abiraterone in clinical studies and in regular patient care for patients with metastatic castration resistant prostate cancer.

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Section: Introductionmentioning

confidence: 96%

Analytical challenges in quantifying abiraterone with LC–MS/MS in human plasma

Benoist

Meulen

Lubberman

et al. 2017

Biomedical Chromatography

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“…Abiraterone acetate is a CYP17‐inhibitor used to treat metastatic castration resistant prostate cancer(mCRPC) . There is accumulating evidence that, in the clinically used dose, exposure correlates well with treatment outcome (2–4) and that a threshold for abiraterone C trough (8.4 ng ml −1 ) is correlated with prostate specific antigen (PSA) response during therapy . In our clinic, Therapeutic Drug Monitoring (TDM) of abiraterone is performed to support treatment, for example, in case of drug–drug interactions .…”

Section: Cyp3a4 Inducers Product Label Advice and Evidence For Drug–mentioning

confidence: 99%

“…during therapy [3][4][5][6]. In our clinic, Therapeutic Drug Monitoring (TDM) of abiraterone is performed to support treatment, for example, in case of drug-drug interactions [7].…”

mentioning

confidence: 99%

A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration‐resistant metastatic prostate cancer

Benoist¹,

Doelen²,

Heine³

et al. 2018

Brit J Clinical Pharma

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Clinicians and pharmacists should be aware of this clinically relevant interaction. The national drug-drug interaction checker does not warn for this interaction, whereas both the Lexicomp® and Micromedex® advice to avoid if possible or to increase the abiraterone dose frequency to twice daily. Carbamazepine should not be combined with abiraterone to avoid underexposure and suboptimal therapy. Therapeutic drug monitoring of abiraterone is useful to guide therapy when drug-drug interactions cannot be avoided.

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“…A flat dose of 1000 mg of abiraterone administered on an empty stomach is recommended based on phase I pharmacokinetic (PK) studies in prostate cancer patients . No dose limiting toxicities were seen up to 2000 mg, but there was a plateau in the pharmacodynamics (PD) effect at doses greater than 1000 mg. A link between abiraterone exposure with PSA response and progression‐free survival in mCRPC has been suggested …”

Section: Novel Androgen Axis Inhibitorsmentioning

confidence: 99%

“…46,47 No dose limiting toxicities were seen up to 2000 mg, but there was a plateau in the pharmacodynamics (PD) effect at doses greater than 1000 mg. A link between abiraterone exposure with PSA response and progression-free survival in mCRPC has been suggested. 48,49 Substantial variability in abiraterone absorption has been observed with up to ninefold differences in serum pharmacokinetic parameters seen within the 1000 mg cohort, which appears to be influenced by timing between dose and food intake. Mean systemic exposure increased as much as fivefold between the fasted and fed patients.…”

Section: Effect Of Fasted Versus Fed State On Abirateronementioning

confidence: 99%

Dose considerations for anti-cancer drugs in metastatic prostate cancer

Crumbaker

2017

Prostate

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Despite a growing number of treatment options, metastatic castrate resistant prostate cancer remains almost universally fatal. Dose individualization ensures patients receive the maximal benefit from each line of treatment potentially leading to improved outcomes, a reduction in quality of life impairment and minimization of premature cessation for avoidable toxicity. Herein, we review drug-specific issues that may be associated with unexpected or unrecognized variations in drug systemic exposure despite the use of protocol doses. In particular, we discuss the potential for under-exposure of docetaxel and cabazitaxel; over-exposure of enzalutamide; and varied absorption of abiraterone acetate.

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Modeling the Relationship Between Exposure to Abiraterone and Prostate-Specific Antigen Dynamics in Patients with Metastatic Castration-Resistant Prostate Cancer

Abstract: The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

Cited by 18 publications

References 30 publications

Analytical challenges in quantifying abiraterone with LC–MS/MS in human plasma

Analytical challenges in quantifying abiraterone with LC–MS/MS in human plasma

A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration‐resistant metastatic prostate cancer

Dose considerations for anti-cancer drugs in metastatic prostate cancer

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