Date of first round report: 1 September 2016 Date of second round report: 30 January 2017



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Pharmacokinetics in healthy subjects

  1. Absorption

    1. Sites and mechanism of absorption


The proposed formulation of palbociclib for marketing takes the form of an IR capsule that is to be taken orally with food. Following administration of a single oral dose of 125 mg of the final Phase III free base palbociclib capsule to healthy males, the median Tmax occurred 8.08 h following dosing and the mean Cmax and AUCinf were 59.6 ng/mL and 1864 ng.h/mL, respectively. The mean t1/2 was 22.05 h and the apparent volume of distribution (Vz/F) and apparent oral clearance (CL/F) values were 2114 L and 67.1 L/h.
      1. Bioavailability

        1. Absolute bioavailability


The absolute oral BA of a 125 mg IR capsule formulation of palbociclib, which contained the initial Phase III freebase, under fasted conditions relative to a 50 mg IV infusion was examined in 14 healthy males as part of Study A5481015. The results indicated that the estimated absolute oral BA of palbociclib was 45.69% (90% CI: 39.25%, 53.19%). In addition, following oral administration, palbociclib geometric mean (GM) CL/F and Vz/F were 86.3 L/h and 3017 L, respectively, whereas, following IV infusion, palbociclib GM CL and Vss were 39.5 L/h and 1008 L, respectively.
        1. Bioavailability relative to an oral solution or micronised suspension


Study A5481009 compared the BA of a 50 mg dose of an oral solution of palbociclib to a 125 mg dose of the isethionate hard capsule IR formulation in 24 healthy males. The dose-normalised GMRs (solution/capsule) for AUCinf and Cmax were 92.78% (90% CI: 85.65%, 100.50%) and 85.68% (90% CI: 75.42%, 97.34%), respectively. Although the dose normalised AUC ratio fell within the bioequivalence (BE) limits (80%, 125%), the lower bound of 90% CI for dose-normalised Cmax was below the lower bound of the BE limit. The median Tmax values were 8 h for the solution and 6 h for isethionate hard capsule, whereas, the mean t1/2 was similar for both treatments and ranged from 22.4 h to 22.7 h.
        1. Bioequivalence of clinical trial and market formulations


A number of studies examined the BE of the various clinical trial and the to-be-marketed formulations. Possibly the most relevant of these, Study A5481020, examined the BE between a single 125 mg dose of the final Phase III commercial free base capsule and a 125 mg dose of either the initial Phase III free base capsule or the isethionate salt form of palbociclib (as a 25-mg capsule and a 100-mg hard capsules), which was used in the Phase 1/2 studies in subjects with cancer, under fasted conditions. The ratios (90% CIs) of the adjusted GMs (final Phase III/initial Phase3) of palbociclib AUCinf and Cmax were 103.44% (98.14%, 109.03%) and 101.24% (91.19%, 112.39%), respectively and as the 90% CIs for the ratios fell entirely within the BE limits (80%, 125%) the two formulations can be considered bioequivalent. In addition, the median Tmax values were 6.00 h for both treatments and the mean t1/2 was similar for the 2 treatments with mean values of 22.2 h and 22.7 h for the final and initial Phase III forms, respectively. For the second comparison, the ratios of the adjusted GMs (final Phase III/isethionate salt) of palbociclib AUCinf and Cmax were 94.80% (89.97%, 99.90%) and 84.78% (76.36%, 94.12%), respectively. Although the 90% CIs for the AUCinf ratio fell entirely within the BE limits, the lower bound of 90% CIs for Cmax was below the lower bound of the BE limit. The median Tmax values were 6.00 h following both treatments and the mean t1/2 values were 22.2 h and 22.4 h for the final Phase III and the isethionate salt forms, respectively.

Two studies, A5481022 and A5481040 examined the effects of particle size (standard and larger) and different levels of lubrication (Levels 1 – 3) on the PKs of the final Phase III capsules. In general, the PK parameters were similar between the different formulations with the AUCinf ranging from 1138 – 1245 ng.h/mL, Cmax from 28.0 – 36.7 ng/mL, t1/2 from 25.3 h – 25.9 h, Vz/F from 3597 – 3992 L and CL/F 100.4 – 109.8 L/h. However, the median Tmax appeared to occurr slightly later following administration of formulations with lubrication levels of 2 or 3 (6.00 h cf. 8.00). Statistical comparisons of the ratios of adjusted GMs (90% CI) for palbociclib AUCinf indicated that in terms of AUC the different formulations were bioequivalent to final Phase III formulation with the standard particle size and lubrication level 1 as the 90% CIs for AUC were contained within the 80% to 125% equivalence limits. By contrast, the ratio of adjusted GMs (90% CI) of palbociclib Cmax were 111.29% (91.48%, 135.41%) for API Level 1, 96.51% (79.32%, 117.42%) for API Level 2, 83.77% (68.90%, 101.86%) for API Level 3, relative to palbociclib API Level 1 formulation, indicating that in terms of Cmax none of the formulations were bioequivalent to the palbociclib API Level 1 formulation.

One other study, A5481009, which has been previously described, compared the BA of two formulations of the initial Phase III capsules, formulated using palbociclib particle sizes of and , to capsules containing the isethionate salt. For the comparison of the freebase small particle capsule and the isethionate capsule, although the 90%CIs for palbociclib AUCinf fell wholly within the BE limits (80%, 125%), the 90% CIs for Cmax did not. By contrast, the isethionate capsule and the freebase large particle capsule were bioequivalent in regards to both the AUC and Cmax values.

        1. Bioequivalence of different dosage forms and strengths


No studies provided.

Comment: The current application is for the registration of 3 dosage strengths of IR capsules, which contain 75 mg, 100 mg or 125 mg of the final Phase III formulation of palbociclib. Although Study A5481032 examined dose proportionality between 4 single dose levels of palbociclib (75mg, 100 mg, 125 mg or 150 – 200 mg final Phase III capsule), no studies have been provided that examine the BE of these 3 dosage strengths nor has the Sponsor applied for a waiver of the requisite studies.
        1. Bioequivalence to relevant registered products


Not applicable.
        1. Influence of food


Two studies, A5481021 and A5481036, examined the influence of food on palbociclib PKs. The first of these studies, A5481021 estimated the BA of a single dose of palbociclib 125 mg (final Phase III form) administered 30 min after either a high-fat, high-calorie meal, a low-fat, low-calorie meal or a moderate-fat, standard calorie meal relative to that seen following a single dose of palbociclib 125 mg given under fasted conditions in 28 healthy males. The results indicated that following a high fat, low fat or moderate fat meal compared to fasted conditions the ratios (90% CIs) of adjusted GMs of palbociclib AUCinf were 120.59% (112.61%, 129.14%), 111.81% (104.29%, 119.87%) and 113.13% (105.60%, 121.19%), respectively. Accordingly, the corresponding 90% CIs for the ratios of the adjusted GMs for AUCinf were contained within the 80% to 125% BE limits when palbociclib was administered under fed low-fat (C) and fed moderate-fat (D) conditions but not under high-fat conditions. For Cmax, the ratios (90% CIs) of adjusted GMs were 137.78% (120.55%, 157.47%), 127.08% (110.92%, 145.60%) and 124.04% (108.43%, 141.88%) for the high fat, low fat and moderate fat conditions, respectively, and the 90% CIs for the ratios of adjusted GMs for Cmax fell outside the BE limits for the upper bound.

Study A5481036 compared the BA of a single oral dose of 125 mg palbociclib, formulated as the final Phase III capsule, 25 min after a moderate-fat, standard calorie meal relative to a 125 mg dose of the isethionate salt form following an overnight fast in 36 healthy males. Under these conditions, the ratios (90% CIs) of the adjusted GMs (fed/fasted) of palbociclib AUCinf and Cmax were 110.93% (106.65%, 115.38%) and 105.20% (100.54%, 110.07%), respectively. As the 90% CIs for the GMRs were completely contained within the (80%, 125%) BE limits the two formulations were bioequivalent.



Comment: It’s interesting to note that the influence of food is not consistent between formulations. For instance, when the final Phase III and the isethionate forms were administered under fasted conditions they were not strictly bioequivalent as the 90% CIs for the GMR of Cmax were not contained within the BE limits, whereas, when the final Phase III form was administered after a moderate-fat, standard calorie meal and the isethionate salt was administered under fasted conditions, as in Study A5481036, the two formulations could be considered bioequivalent in regards to both AUC and Cmax.
        1. Dose proportionality


The dose proportionality of 4 single oral dose levels of palbociclib (75mg, 100 mg, 125 mg or 150 – 200 mg final Phase III capsule) was examined in healthy Japanese volunteers in the fed state (Study A5481032). The results indicated that palbociclib AUCinf and Cmax increased with increasing dose from 75 mg to 150 mg with the increases appearing to be dose-proportional. Further evidence, which provided support for dose-proportionality, was presented in the form of the superimposition of dose normalised concentration-time profiles and box-plots of the individual Cmax(dn) and AUCinf(dn) demonstrating the relative consistency in the central tendency and range of the observed parameters across doses.
        1. Bioavailability during multiple-dosing


No studies examined multiple dosing in healthy subjects.
        1. Effect of administration timing


Not examined.
      1. Distribution

        1. Volume of distribution


Following administration of a single oral dose of 125 mg of the final Phase III capsule with a high fat, high-calorie breakfast in healthy subjects, the Vz/F (%CV) was 2114 L (17).
        1. Plasma protein binding


Two in vitro studies, RR764-04174 and PF-05089326_17Dec12_104347, examined the binding of palbociclib to human plasma proteins. The results indicated that palbociclib is moderately bound to plasma proteins with an average protein binding of 85% as measured in vitro using equilibrium dialysis. By contrast, binding of palbociclib (500-5000 ng/mL) to human serum albumin and α1-acid glycoprotein was low, with mean values of 37.8% and 35.4%, respectively.
        1. Erythrocyte distribution


The human blood-to-plasma concentration ratio for palbociclib was 1.63, suggesting a modest preferential distribution into blood cells relative to the plasma compartments. In addition, the Mass Balance study, (Study A5481011), identified low levels of radioactivity in red blood cells, compared with those in plasma and whole blood, indicating that the amount of radioactive moieties partitioning into erythrocytes was relatively small.
        1. Tissue distribution


Based on the volume of distribution in can be assumed that palbociclib is highly distributed to the tissues.
      1. Metabolism

        1. Interconversion between enantiomers


Not applicable.
        1. Sites of metabolism and mechanisms / enzyme systems involved


Three in vitro studies, PD-0332991_05Mar13_095443, PD-0332991_18Sep13_170350 and PD-332991_10Sep13_193503 examined the primary metabolic pathways of palbociclib. In human hepatocytes, palbociclib was primarily metabolised via oxidation, sulphonation, glucuronidation, and reduction. Experiments with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that metabolism of palbociclib was mediated mainly by CYP3A and SULT family 2A member 1 (SULT2A1) enzymes.
        1. Non-renal clearance


In the Mass Balance study, three metabolites were responsible for 45% of the dose excreted in faeces. The sulphamic acid of palbociclib (M11, PF-06754233), was the major metabolite in all subjects accounting for 25.8% of the dose. One subject showed M11 as the only dominant faecal metabolite at 46% of dose. A carboxylic acid, M16, derived from sequential oxidative metabolism of the piperazine ring, was the next most abundant metabolite at 14.2% of dose, and M20, a cyclopentyl ring-hydroxylated metabolite of the lactam (M17), accounted for 5.0% of the dose. Palbociclib was present in faeces of 5 of the 6 subjects at levels ranging from 0.5% to 5.1% (with a mean of 2.3%) of dose. The formyl- and acetyl- derivatives of palbociclib, M26 and M12, respectively, were each present at 1.3% of dose.
        1. Metabolites identified in humans: active and other


The Mass Balance study, (Study A5481011) that following a single dose of [14C] palbociclib to healthy subjects, palbociclib was the primary drug-related material in circulation, accounting for 23.3% of the plasma radioactivity. M22 was the most abundant metabolite at 14.8% of circulating radioactivity. The other primary clearance metabolites M11, M26, and M12, were present at low levels (1.3%, 1.5%, and 1.0%, respectively). M16, a major faecal metabolite, was present in plasma at 2.6%, whereas M20 was not detected. Three minor radiochemical peaks characterised were the lactam of palbociclib (M17, PF-05089326), a dilactam of palbociclib (M24), and a metabolite with the pyrido-piperazine substructure cleaved (M25), at 4.7%, 4.4% and 2.3%, respectively. A single radiochemical peak (U) accounting for 6.2% of the circulating radioactivity did not yield an assignable mass spectrum.

Question: As M22 is the most abundant circulating metabolite (responsible for 14.8% of circulating radioactivity), does the Sponsor have information regarding its activity?


Active metabolite

The pharmacological activity of and systemic exposure to the circulating oxidative metabolite of palbociclib, PF-05089326, was investigated using in vitro techniques and as part of Studies A5481009 and A5481011. PF-05089326 was shown to have comparable potency with that of palbociclib for inhibiting CDK 4 (IC50=5.4 nM or 2.4 ng/mL) and CDK 6 (IC50=16.2 nM or 7.3 ng/mL) (Studies REG-RR 700-00180 and 75760087).
        1. Pharmacokinetics of metabolites


Following a 125 mg dose of the initial Phase III, free base capsule with a particle size of to healthy males the Cmax and AUCinf values for PF-05089326 were 7.03 ng/mL and 110.8 ng.h/mL, respectively. PF-05089326 Tmax was 4.00 h, representing metabolite formation and the mean t1/2 value was 20.4 h. The metabolite to parent ratio, as reflected in MRAUCinf value, was approximately 0.08.
        1. Consequences of genetic polymorphism


Not examined.
      1. Excretion

        1. Routes and mechanisms of excretion


Following administration of [14C]-palbociclib (125 mg containing approximately 100 μCi) to 6 healthy males, approximately 74% of the dose was excreted in faeces and 18% in urine. The amount of palbociclib excreted unchanged in the urine over the 192 h collection period was 6.9% indicating that urinary excretion was only a minor route for palbociclib elimination and the mean CLr was 5.9 L/h.
        1. Mass balance studies


During Study A5481011, excreta samples were collected to at least 216 h post-dose for all six participating subjects. Excreta collection was continued for 2 subjects for up to 360 h post-dose. At the end of the collection period, the overall median mass balance of the radioactive dose excreted was 91.6%, with a median of 17.5% recovered in urine and a median of 74.1% recovered in faeces.
        1. Renal clearance


The Mass Balance study identified that palbociclib and 2 isomeric mono-hydroxylated metabolites of palbociclib (M23a, M23b) were the major urinary components at 3.7% and 3.5%, respectively, of dose. The glucuronide of palbociclib (M22) was present in urine at 1.5% of dose. Two (2) radiochemical peaks (U) at retention times of 30.2 and 45.5 min representing 1.1% of dose, were not characterised by mass spectrometry.
        1. Intra and inter individual variability of pharmacokinetics


The 2-compartment model population PK (popPK) model, which is described in PMAR-EQDD-A548b-DP4-269 and was developed based on a dataset that comprised 2208 PK observations from 184 cancer patients treated with palbociclib provided estimates for the inter-subject variability on CL/F, V2/F, inter-compartmental clearance (Q/F) and absorption rate constant (Ka) of approximately 36.2%, 30.2%, 126.1% and 83.6%, respectively. The intra-subject variability was estimated to be 0.317.
      1. Pharmacokinetics in the target population

        1. Breast cancer


Part of Study A5481003 examined the PKs of palbociclib (125 mg QD isethionate capsules) when administered to steady-state in 12 postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Results indicated that palbociclib appeared to reach steady-state exposures on or before Day 8, based on similar trough (pre-dose) concentrations on Day 8 through Day 14 in Cycle 1. When administered to steady state, the geometric mean CL/F and Vz/F of palbociclib were 63.08 L/h and 2583 L, respectively. In this population, the mean palbociclib Cmax, AUC24, t1/2 and Tmax values were 115.8 ng/mL 1982 ng.h/mL, 28.8 h and 7.9 h, respectively.
        1. Other cancers


Two further studies, A5481001 and A5481010 examined the PKs of palbociclib in patients with advanced solid tumours, including some subjects with breast cancer. For instance, in Study A5481001 of the 74, predominantly White (n = 69), subjects who received at least 1 dose of palbociclib, six had breast cancer. The primary objectives of this study were to identify dose limiting toxicities (DLT) and maximum tolerated dose (MTD) following doses of 25 to 225 mg palbociclib QD for 14 to 21 days. Unfortunately, as some plasma samples were not obtained as per protocol, the planned PK analyses could not be performed. However, in 13 subjects who received either multiple doses of 125 mg or 200 mg palbociclib QD, plasma PK parameters could be determined (with the results for the 200 mg dose being corrected to the 125 mg dose level for reporting purposes) and indicated that the median Tmax, mean t1/2, Vz/F and CL/F values were 4 h, 26.5 h, 3103 L and 86.1 L/h, respectively; the accumulation ratio following multiple dosing was 2.4. Renal excretion of unchanged palbociclib was a minor route of elimination with approximately 1.7% of the drug excreted unchanged in urine over the 10 h collection period in the 125 mg and 200 mg dose group patients combined (CLR = 6.59 L/h). Study A5481001 also examined the effect of a high fat meal on the PKs of palbociclib and the results indicated that the adjusted GM palbociclib AUC(0-10) and Cmax were higher in the fed state than in the fasted state (AUC(0-10): 370.5 vs. 290.5 ng.h/mL, respectively; Cmax: 59.7 vs. 42.8 ng/mL, respectively). In terms of Tmax, t1/2, Vz/F and CL/F the results of this study were similar to the results of Study A5481003.
      1. Pharmacokinetics in special populations


Comment: The number of clinical trials that specifically examined the PKs of palbociclib in special populations was somewhat limited; therefore, the following discussion is primarily based on the results of the PopPK analysis PMAR-EQDD-A548b-DP4-269.
        1. Pharmacokinetics in subjects with impaired hepatic function


Although Study A5481013 examined the PKs of palbociclib in patients with hepatic impairment all that is provided in the evaluation materials in regards to this study is a SUSPECT ADVERSE REACTION REPORT.

Therefore, based on the PopPK analysis, which included 142 patients with normal liver function, 40 patients with mild hepatic impairment and 1 patient with moderate hepatic impairment, the liver enzymes including baseline alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin values were not significant covariates of palbociclib CL/F. Therefore the sponsor recommends that no dose adjustment is necessary for patients with mild hepatic impairment as defined based on the National Cancer Institute (NCI) scale.

Question: Can the sponsor please provide the complete clinical trial report for Study A5481013, which examined the effects of hepatic impairment on palbociclib PKs?

        1. Pharmacokinetics in subjects with impaired renal function


No clinical studies specifically examined the effects of renal impairment on palbociclib PKs. However, given that renal clearance is responsible for approximately 6.9% of palbociclib excretion over a 192 h period after dosing, renal impairment is unlikely to significantly affect palbociclib PKs. This was confirmed in the PopPK analyses, which included 81 patients with normal renal function, 73 patients with mild renal impairment and 29 patients with moderate renal impairment and identified that creatinine clearance (range: 29-185 mL/min) was not a significant covariate on CL/F of palbociclib.
        1. Pharmacokinetics according to age


Not examined.
        1. Pharmacokinetics related to genetic factors


Not examined.
        1. Pharmacokinetics in other special population/with other population characteristic

Race

Two studies examined the PKs of palbociclib in Japanese subjects. The first of these, Study 5481032, investigated the effect of ethnicity on the PK of a single oral dose of palbociclib 125 mg given under fed conditions to healthy Japanese subjects and demographic-matched healthy non-Asian subjects. The results indicated that although median Tmax (6.05 h and 6.02 h) and mean t1/2 values (22.8 h and 23.9 h) were similar in healthy Japanese and non-Asian subjects, palbociclib GM AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese subjects than in matched non-Asian subjects. Variability in palbociclib PK parameters was also similar between cohorts as the inter-subject variability (%CV) values for AUCinf and Cmax in Japanese subjects were 24% and 33%, respectively, and 26% and 39%, respectively, for the non-Asian population.

Study A5481010 examined palbociclib PKs following doses of 100 mg or 125 mg in a population of 12 Japanese patients with advanced solid tumours, including 3 patients with breast cancer. Following a single oral dose of 100 mg or 125 mg palbociclib, the median Tmax occurred at 4-5 h post-dosing. Mean t1/2 values for the two doses were 25.7 and 23.9 h, respectively, and GM CL/F values were 96.4 and 50.3 L/h, and GM Vz/F were 3514 and 1730 L, respectively. After multiple oral doses of 100 mg or 125 mg palbociclib QD, the median Tmax was generally achieved by 4 h post-dosing and the mean t1/2 values were 23.8 h and 23.2 h, respectively, whereas, the accumulation ratios were 2.1 and 1.9 for the 100 mg and 125 mg dose groups, respectively.


Body weight

The PopPK analyses indicated that although baseline body weight (range: 37.9-123 kg) and age (range: 22-89 years) were significant covariates on CL/F, and baseline body weight was a significant covariate on apparent volume of distribution in the central compartment (V2/F), these covariates were not considered clinically significant.
      1. Population pharmacokinetics

        1. PopPK analysis ID


As previously described, Study PMAR-EQDD-A548b-DP4-269 outlined the development of a popPK model, which described the PKs of palbociclib in patients with cancer. Palbociclib PK was reasonably well characterised by a 2-compartment model and a typical cancer patient (i.e. body weight of 73.7 kg at age of 61 years old) was estimated to have a CL/F and V2/F of 60.2 L/h and 2710 L, respectively.
      1. Pharmacokinetic interactions

        1. Itraconazole – CYP3A4 inhibitor


Study A5481016 investigated the effect of multiple 200 mg QD doses of the CYP3A4 inhibitor, itraconazole on the PK of a single oral 125 mg dose of palbociclib in healthy subjects. The results indicated that although there was little change in median Tmax values when palbociclib was administered alone (8.1 h) compared to when it was co-administered with itraconazole (7.4 h), mean palbociclib t1/2 values increased from 22.1 h to 33.9 h following co-administration with itraconazole. In addition, the adjusted GM palbociclib AUCinf and Cmax values following co-administration of itraconazole were approximately 87% and 34% higher, respectively, compared to when palbociclib was administered alone. The apparent oral clearance of palbociclib decreased from 67.09 L/h when palbociclib was administered alone to 36.18 L/h when palbociclib was co-administered with itraconazole.
        1. Rifampin – potent CYP3A4 inducer


Study 5481017 investigated the effect of multiple doses of 600 mg rifampin QD, a potent CYP3A4 inducer, on the PK, of a single oral dose of palbociclib 125 mg given under fasted conditions. The results indicated that following co-administration with rifampin, median palbociclib Tmax decreased from 8.0 h to 3.0 h compared to when palbociclib was administered alone and mean t1/2 decreased from 22.6 h to 7.8 h. In addition, palbociclib CL/F was approximately 6.3-fold higher following co-administration with rifampin compared to when palbociclib was administered alone and the ratios (90% CIs) of the adjusted GMs for palbociclib AUCinf and Cmax were 15.47% (12.03%, 19.88%) and 30.17% (23.51%, 38.72%), respectively.
        1. Modafinil and pioglitazone - CYP3A inducers


Study A5481039 examined the effect of multiple 400 mg doses of the moderate CYP3A inducer modafinil on the PK of a single oral 125 mg dose of palbociclib administered in the fed state. This study also proposed to investigate the effect of multiple doses of the weak CYP3A inducer pioglitazone on the PK of a single oral 125 mg dose of palbociclib. Median palbociclib Tmax occurred slightly later (approximately 2 h later) in the presence of steady-state modafinil compared to when it was administered alone and mean t1/2 for palbociclib decreased from approximately 22.8 h to 19.4 h in the presence of steady-state modafinil. By contrast, the GM apparent oral clearance of palbociclib increased from 69.48 L/h when palbociclib was administered alone to 102.5 L/h when co-administered with steady-state modafinil; the ratios of the adjusted GMs for palbociclib AUCinf and Cmax (90% CI) were 68.21% (61.62%, 75.51%) and 88.51% (80.55%, 97.25%), respectively, when palbociclib was co-administered with steady-state modafinil (Test) as compared to its administration alone. As the Sponsors considered that the effects of modafinil on palbociclib exposure were marginal, the study phases, which were to examine the effects of pioglitazone on palbociclib PKs, were not undertaken.
        1. Midazolam – CYP3A4 substrate


Study A5481012 examined the effect of multiple doses of 125 mg palbociclib QD on the PKs of a single, 2mg, oral dose of midazolam in healthy women of non-childbearing potential. When midazolam was co-administered with palbociclib at steady-state, GM Cmax and AUCinf values for midazolam increased by 37.5% and 61.1%, respectively compared to when it was administered alone. By contrast, the median Tmax values (0.5 h) for midazolam were the same whether midazolam was administered alone or with palbociclib, whereas, the mean t1/2 value for midazolam was slightly longer with mean values of 7.2 and 8.2 h for midazolam alone and when co-administered with palbociclib, respectively.

Comment: Study A5481012 did not evaluate the effect of midazolam on palbociclib PKs.
        1. Tamoxifen - CYP2D6 and CYP3A4 substrate


Study A5481026 evaluated the effect of multiple doses of 20 mg tamoxifen, which is used as a treatment for breast cancer and is a CYP2D6 and CYP3A4 substrate, on the PK of a single oral dose of 125 mg palbociclib in healthy males. For the full analysis set, the geometric mean ratios (GMRs) for Cmax and AUCinf were 1.20- and 1.13-fold, respectively, when palbociclib was co-administered with steady-state tamoxifen compared to when it was administered alone and the median Tmax was 7.98 h and 6.10 h, respectively. As substantially lower exposure was observed in some subjects (low-liers), a second PK analysis was undertaken that excluded this group and for the population excluding low-liers, the GMR for Cmax and AUCinf were 1.16- and 1.08-fold, respectively, when palbociclib was co-administered with steady-state tamoxifen compared to when it was administration alone. A further PK analysis was conducted following the removal of 2 subjects who had been identified as poor metabolisers of CYP2D6 PMs; however, the exclusion of these subjects did not alter the interpretation of these results.

Comment: Study A5481026 did not evaluate the effect of palbociclib on tamoxifen PKs.
        1. Letrozole – CYP2A6 and CYP3A4 substrate


Study A5481003 examined the PKs of palbociclib and letrozole, a substrate of CYP2A6 and CYP3A4, following co-administration of 125 mg and 2.5 mg QD, respectively, to postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Co-administration of palbociclib with letrozole had no effect on the PKs of palbociclib at steady-state, compared to when palbociclib was administered alone; the GMRs for palbociclib AUC24 and Cmax (90% CI) were 97.54% (90.16%-105.52%) and 93.60 % (84.24%-104.00%), respectively. Similarly, co-administration of letrozole with palbociclib had no effect on letrozole AUC24 (GMR [90% CI] = 89.84% [84.54%-95.47%]) or Cmax (91.30% [85.21%-97.83%]), compared to when letrozole was administered alone.
        1. H2-antagonists, PPI and antacids


Study A5481038 investigated the effect of: 20 mg famotidine (an H2-receptor antagonist) given 10 h before and 2 h after palbociclib; the protein pump inhibitor (PPI) rabeprazole sodium given 40 mg QD for 6 days before and 4 h prior to palbociclib; or 30 mL of the antacid Mi-Acid Maximum Strength Liquid given 2 h before or after palbociclib administration in healthy males. The results indicated that the GMRs for palbociclib AUCinf and Cmax (90% CI) were 96.02% (87.90%, 104.89%) and 95.00% (79.23%, 113.90%), respectively following administration of palbociclib with famotidine relative to palbociclib administered alone. By contrast, following administration with the PPI, the GMRs for palbociclib AUCinf and Cmax (90% CI) were 86.85% (79.50%, 94.87%) and 59.18% (49.36%, 70.95%), relative to when palbociclib was administered alone. When antacid was administered either 2 h before or 2 h after palbociclib under fed conditions, the median Tmax values for palbociclib increased slightly with values of 6.0 h, 8.0 h and 8.00 h for palbociclib alone, antacid 2 h before and 2 h after, respectively, whereas, there was little change in the AUCinf and Cmax values of palbociclib under either of these conditions as the 90% CIs for the GMR were contained within the (80%, 125%) BE limits.

Study A5481018 investigated the potential effect of increased gastric pH resulting from treatment with the PPI rabeprazole sodium 40 mg QD, on the PK of a single oral 125-mg dose of palbociclib given under fasted conditions. For the full analysis set population, co-administration of palbociclib plus QD rabeprazole decreased palbociclib exposures as measured by AUCinf and Cmax by approximately 56% and 75%, respectively and the median Tmax was delayed (7.00 h cf. 24.0 h). By contrast, the mean t1/2 was similar with values of 21.97 h when palbociclib was administered alone and 22.45 h when it was co-administered with rabeprazole.



The PopPK analysis, PMAR-EQDD-A548b-DP4-269, also examined the effects of co-administration of acid reducing agents, including proton pump inhibitors, H2 receptor antagonist and other types of antacids on the PKs of the palbociclib isethionate salt capsules and concluded that co-administration of these drugs with palbociclib did not significantly affect the relative BA or absorption of palbociclib.
        1. Clinical implications of in vitro findings


Studies of human liver microsomes identified that palbociclib and its circulating metabolite, PF-05089326, demonstrated time-dependent inhibition of CYP3A enzyme(s). By contrast, further studies indicated that clinically relevant interactions were unlikely to occur with drug substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. In addition, palbociclib displayed low potential to inhibit CYP2A6 in human liver microsomes and it did not cause induction of CYP1A2, CYP2B6, CYP2C8, or CYP3A4 in human hepatocytes at concentrations exceeding the unbound palbociclib steady-state Cmax at therapeutic doses in humans by greater than 50-fold. Palbociclib also showed low potential for inhibiting the activities of selected UGT enzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, BSEP, OAT1, OAT3, and OCT2) at clinically relevant concentrations.
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