Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

This is a fixed sequence study with 5-sequential treatment periods in healthy volunteers. Each volunteer will receive 5 single doses of AZD9496 in different forms, formulations and doses.

1. Treatment period 1 will assess AZD9496 Variant A: 100mg.
2. Treatment period 2 will assess AZD9496 Reference: 100mg.
3. Treatment period 3 will assess one of AZD9496 Variants, B, C or D: 100mg.
4. Treatment period 4 will assess one of AZD9496 Variants, B, C or D: 100mg.
5. Treatment period 5 will assess one of AZD9496 Variants A, B, C or D: \*300mg. \*Based on a review of PK and safety results from Treatment Periods 1, 3 and 4, a lower dose of 200 mg may be administered in Treatment Period 5

AZD9496 (Reference)

AZD9496 Variant A

AZD9496 Variant B

AZD9496 Variant C

AZD9496 Variant D

Dr. Ronald Goldwater

This is a phase 1 open label single centre study of AZD9496 administered orally in healthy volunteers. The study design involves single administration of different forms, formulations and doses of AZD9496. The study is designed to investigate these different AZD9496 variants. The study will evaluate the pharmacokinetic profiles and the safety and tolerability of the different forms, formulations and doses of AZD9496

This is a fixed sequence study with 5-sequential treatment periods in healthy volunteers. Each volunteer will receive 5 single doses of AZD9496 in different forms, formulations and doses.

A phase 1, open-label, single centre study to assess the pharmacokinetics, Safety and tolerability of different forms, formulations and doses of AZD9496 in healthy volunteers. This is a fixed sequence study with 5-sequential treatment periods. Each subject will receive 5 single doses of AZD9496 in different forms, formulations and doses.

* Treatment period one will assess AZD9496 Variant A: 100mg.
* Treatment period two will assess AZD9496 Reference form: 100mg.
* Treatment period 3 will assess one of AZD9496 Variants, B, C or D: 100mg.
* Treatment period 4 will assess one of AZD9496 Variants, B, C or D: 100mg.
* Treatment period 5 will assess one of AZD9496 Variants A, B, C or D: \*300mg. \*Based on a review of pharmacokinetic and safety results from Treatment Periods 1, 3 and 4, a lower dose of 200 mg may be administered in Treatment Period 5.

A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects

A Phase I Study to Evaluate the Pharmacokinetic and Safety Profile of AZD9496 Following Single Dose Administration of Different Forms and Formulations in Healthy Subjects

To evaluate maximum observed plasma concentration (Cmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.

To evaluate the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC (0-t) of AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation

To evaluate maximum plasma concentration (Cmax) of capsule variants by comparing with reference AZD9496

To evaluate area under curve from time zero to time with last observation (AUC0-t) of variants by comparing with reference AZD9496

To evaluate area under the curve from time zero to time infinity (AUC 0-infinity) of variants by comparing with reference AZD9496

To evaluate area under the curve from time zero to infinity (AUC 0-infinity) for AZD9496 and its metabolites

To evaluate time to reach maximum observed plasma concentration (Tmax) for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.

To evaluate effective half-life (t½,eff), for AZD9496 and its metabolites M3 and M5 following administration of different AZD9496 formulations and compare with a reference formulation.

To evaluate metabolite to parent ratios (MRAUC0-t, MRCmax, MRAUC) at each treatment period.

Parexel

AstraZeneca

Serious adverse events (SAEs) were recorded from the signing of the informed consent and adverse events (AEs) were recorded from enrollment until the final follow-up visit.

Note: A total of 4 participants reported at least one AE. Of the 4 participants, 1 participant reported two AEs "Rhinorrhoea" and "Body tinea" associated with treatments Variant A and B, respectively.

Participants received AZD9496 - Variant A (100 mg).

Treatment Period 1

Participants received AZD9496 - Reference (100 mg).

Treatment Period 2

Participants received AZD9496 - Variant B (100 mg).

Treatment Period 3

Participants received AZD9496 - Variant C (100 mg).

Treatment Period 4

Participants received AZD9496 - Variant B (300 mg).

Treatment Period 5

All enrolled participants who received at least one dose of AZD9496.

All Participants

Age, Continuous

Male

Female

Sex/Gender, Customized

Data from all analysed secondary pharmacokinetic parameters are presented.

AZD9496 Global clinical leader

AZD9496

Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable.

Pharmacokinetics: Maximum Plasma Concentration (Cmax) for AZD9496 and Its Metabolites at Each Treatment Period.

Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for AZD9496 and Its Metabolites at Each Treatment Period

Participants received AZD9496 - Variant A (100 mg) in Treatment Period 1.

DN Ratio - Variant A (100 mg): Ref (100 mg)

Participants received AZD9496 - Variant B (100 mg) in Treatment Period 3.

DN Ratio - Variant B (100 mg) : Ref (100 mg)

Participants received AZD9496 - Variant C (100 mg) in Treatment 4.

DN Ratio - Variant C (100 mg) : Ref (100 mg)

Pharmacokinetics: Maximum Plasma Concentration (Cmax) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

Participants received this treatment in Treatment Period 4

AZD9496 - Variant C (100 mg)

Pharmacokinetics: Area Under the Curve From Time Zero to Time With Last Observation (AUC0-t) for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

The PK analysis set consisted of all subjects in the safety analysis set for whom at least 1 of the primary PK parameters for AZD9496 could be calculated for at least Treatment Period 2 and 1 other treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Time to Reach Maximum Observed Plasma Concentration (Tmax) for AZD9496 and Its Metabolites at Each Treatment Period.

The PK analysis set consisted of all subjects in the safety analysis set for whom at least 1 of the primary PK parameters for AZD9496 could be calculated for at least Treatment Period 2 and 1 other treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data. Data not available for all participants.

Effective Half-life ( t½,Eff) for AZD9496 and Its Metabolites at Each Treatment Period

M3 - MRAUC(0-t)

M5 - MRAUC(0-t)

M3 - MRCmax

M5 - MRCmax

M3 - MRAUC

M5 - MRAUC

Metabolite to Parent Ratios (MRAUC0-t, MRCmax, MRAUC) at Each Treatment Period.

Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants.

Pharmacokinetics: Area Under the Curve From Time Zero to Infinity for Variant A, B and C of AZD9496 Compared to the AZD9496 Reference

Pharmacokinetics: Area Under the Curve From Time Zero to Infinity (AUC 0-infinity) for AZD9496 and Metabolites at Each Treatment Period

AZD9496 AUC 0-12 Hours

AZD9496 AUC 0-24 Hours

M3 AUC 0-12 Hours

M3 AUC 0-24 Hours

M5 AUC 0-12 Hours

M5 AUC 0-24 Hours

Safety set with 1 primary PK parameter for AZD9496 calculable for Treatment Period 2 and 1 other period. For AUC 0-inf, a predefined R2adj \>0.8 (the goodness of fit parameter for regression estimate of elimination rate constant lambda z used in the AUC 0-inf calculation) was used to determine if the individual AUC estimate was reportable. Data not available for all participants. Where less than 3 participants contribute data, the PK parameter was not calculated.

Pharmacokinetics: AUC From Time Zero to 12 and 24 Hours Post-dose for AZD9496 and Its Metabolites at Each Treatment Period

Pharmacokinetics: The Terminal Elimination Half-life (t½,λz) for AZD9496 and Its Metabolites at Each Treatment Period

Too few data points available. Data not calculated for Vss/F for M3 and M5 .

Pharmacokinetics: Apparent Volume of Distribution (Vss/F) of AZD9496 and Its Metabolites at Each Treatment Period

Too few data points available. CL/F not calculated for M3 and M5. Where less than 3 participants contribute data, the PK parameter was not calculated.

Pharmacokinetics: Apparent Oral Clearance (CL/F) of AZD9496 and Its Metabolites at Each Treatment Period

Too few data points available and so λz not calculated for all participants. Where less than 3 participants contribute data, the PK parameter was not calculated.

Pharmacokinetics: Apparent Terminal Elimination Rate Constant (λz) of AZD9496 and Its Metabolites at Each Treatment Period

Data points not available for all participants. MRT not calculated for M3 and M5 metabolites. Where less than 3 participants contribute data, the PK parameter was not calculated.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects	NCT02780713	Breast Cancer	AZD9496 (Refere... AZD9496 Variant... AZD9496 Variant... AZD9496 Variant... AZD9496 Variant...	18 Years - 65 Years	AstraZeneca
A Study to Assess the Pharmacokinetics and Safety of Different Forms and Formulations of AZD9496 in Healthy Subjects	NCT02780713	Breast Cancer	AZD9496 (Refere... AZD9496 Variant... AZD9496 Variant... AZD9496 Variant... AZD9496 Variant...	18 Years - 65 Years	AstraZeneca

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