Clinical Pharmacokinetics and Pharmacodynamics of Fostamatinib and Its Active Moiety R406

Absorption

Considering the low aqueous solubility of R406, fostamatinib was synthesized and tested in preclinical and clinical studies [48]. Fostamatinib was designed as a methylene-phosphate prodrug that is cleaved by alkaline phosphatase at the apical brush-border membranes of intestinal enterocytes to its active moiety R406, as shown in Fig. 3 [48]. After oral administration, fostamatinib was rapidly and completely hydrolyzed to R406 and absorbed within 1–2 h, and negligible concentrations of fostamatinib were found in the plasma. The absolute bioavailability of R406 is determined to be 55% after a single oral dose of 150 mg of fostamatinib and a 100-µg intravenous dose of R406 in healthy subjects [49,50,51]. Several studies investigated whether R406 and fostamatinib were a substrate of absorption-related transporters. An in vitro assay using a polarized Caco-2 cell monolayer showed that R406 is a substrate of P-glycoprotein (P-gp) from the basolateral to the apical compartment in a concentration-dependent manner [52]. In contrast, another in vitro assay showed that breast cancer resistance protein (BCRP) did not transport R406 and fostamatinib [49].

Fig. 3figure 3

Graphical scheme of fostamatinib pharmacokinetics. Fostamatinib was designed as a prodrug cleaved to R406 by alkaline phosphatase in the intestine. R406 was mainly metabolized by cytochrome P450 (CYP) 3A4 and UGT1A9 in the liver. In human plasma, R406 and other three metabolites (M647, M633, and M537) were detected; however, these three accounted for less than 3%. In the human mass balance study, almost 80% of the radioactivity was recovered in feces, which consisted of two primary metabolites: one was R406 and the other was M413; the 3,5-benzene diol metabolite of R406. The other 20% of metabolites were eliminated into urine as an N-glucuronide R406 (M647)

A phase I study in healthy adults examined the effect of diet (high-fat or high-calorie breakfast) on the absorption of fostamatinib tablets [53]. Even though there was a decline in the rate of absorption, as shown by a delayed time to maximum concentration [tmax] (fasting: 1.39 h, fed: 3.22 h) and lower maximum concentration [Cmax] (fasting: 605 ng/mL, fed: 363 ng/mL), the area under the the plasma concentration–time curve from dosing to infinity (AUC0→∞) of R406 was similar (fasting: 6490 ng·h/mL, fed: 7140 ng·h/mL), and the 90% confidence interval for the ratio of the geometric means in both conditions was within the acceptable equivalency range (Table 1) [53].

Table 1 Pharmacokinetic parameters of R406Distribution

R406 is distributed to extravascular sites and the volume of distribution at a steady state is found to be 256 ± 92 L, based on the results of the radiotracer study [50, 51]. An in vivo study showed that R406 is widely distributed in all tissues, with the exception of the central nervous system [54]. This could be explained by R406 being a substrate of P-gp, which acts as an efflux pump at the blood–brain barrier [52]. R406 distributes reversibly into the blood cell, and the red blood cell-to-plasma concentration ratio is approximately 2.6 [54, 55].

In vitro studies showed that R406 had a mean binding of 96.3% to purified human serum albumin (HSA) and that to purified alpha-1 acid glycoprotein was 75.5%; hence R406 is highly bound to plasma proteins [50, 51, 54]. Although HSA is known to have several drug-binding sites [56], the information on the binding sites of HSA and R406 is not available. When R406 was administered in combination with drugs that bind more tightly to the same site, an increase in the concentration of unbound R406 should be concerned. Moreover, low albumin levels associated with malnutrition or cirrhosis may also affect the increase in unbound R406 concentration. Martin et al. showed that the patients with cirrhosis had a higher unbound R406 ratio compared with healthy patients [57]. Further study is needed to explore the R406 binding site to HSA and the correlation between an elevated unbound R406 concentration and the frequency and severity of adverse events.

Metabolism

For evaluating the major metabolic pathways of R406, several in vitro studies and a human mass balance study in healthy subjects were performed [48]. A summary of the metabolic pathways after fostamatinib administration is shown in Fig. 3. After incubation of R406 with human hepatic microsomes in vitro, R406 levels gradually decreased, and the para-O-demethylated metabolite of R406 (R529) was identified. When the effects of the chemical inhibitors of cytochrome P450 [CYP] (ketoconazole, 3A4; furafylline, CYP1A2; quinidine, CYP2D6; sulfaphenazole, CYP2C9; and 3-N-benzylnirvanol, CYP2C19) on R406 metabolism were assessed, only ketoconazole could inhibit R529 production [48, 58]. Thus, R406 was predominantly metabolized by CYP3A4. Additionally, direct N-glucuronide conjugates of R406 (M647) were observed after incubation in hepatic microsomes with UDP-glucuronic acid, and further studies revealed that UGT1A9 was involved in this reaction [48, 54]. Consistent with in vitro findings, after C14-labeled fostamatinib was administered in a mass balance study, three minor peaks—M647, O-glucuronide conjugate R529 (M633), and sulfate conjugate of R529 (M537)—were identified [48]. However, these metabolites (M647, M633, and M537) accounted for less than 3% of the total radioisotopes in human plasma [48]. In summary, R406 is mainly metabolized by CYP3A4 and UGT1A9 in the liver. Although there is no information on which metabolic pathway predominantly metabolizes R406, a drug–drug interaction with CYP3A4 inhibitors and inducers should be considered in clinical practice.

Elimination

In the human mass balance study, 80% of the radioactivity was recovered in feces within 96 hours, and 19.3% was recovered in urine within 72 h. Therefore, hepatic clearance was a major clearance pathway of R406 [48]. In cynomolgus monkeys, 68.9% of the administered radioactivity was transported into the bile. Biliary metabolites consisted of M647, M633, and M537 [59]. In pooled feces, two major radioactive peaks were observed via liquid chromatography-tandem mass spectrometry; one was R406 (m/z 471), and the other was M413; the 3,5-benzene diol metabolite of R406. Although fostamatinib, R406, M647, and conjugates of R529 (M633 and M537) may all be present in the intestinal tract, production of M413 was observed only from R529 in the incubation of human feces under in vitro anaerobic conditions [48, 59]. These results indicate that the biliary metabolite (M647, M633, and M537) once hydrolyzed to R406 and R529, then R529 was O-demethylated and dehydroxylated by anaerobic gut bacteria. In urine, the major metabolite was M647, and a negligible level of R406 was detected (Fig. 3).

Among six healthy male subjects (aged 19–35 years) who participated in the mass balance study, the ratio of R406 to M413 in feces varied among the individuals (R406:M413; 1:0.18–11.6) [48]. This may be due to individual differences in the metabolic activity of CYP3A4, which metabolizes R406 to R529, or that of gut microbiota, which metabolizes R529 conjugates to M413. Given that R529 and its conjugates were not detected in feces, the occurrence of the former was more likely [48]. In addition, diarrhea is a common AE associated with fostamatinib therapy. Although the mechanism of this AE has not been elucidated, it cannot be denied that metabolites excreted and retained in the intestinal tract might cause intestinal toxicity. The relationship between diarrhea and the individual differences in fecal metabolites should be investigated.

PK Profiles in Healthy Volunteers and Patients

Baluom et al. reported three clinical studies to evaluate the human PK properties of R406 in healthy subjects [53]. The PK parameters are summarized in Table 1. The first was a single ascending dose (80, 250, 400, 500, 600 mg) study of orally administered R406 besylate formulated in a d-alpha-tocopheryl-polyethylene-glycol-1000 succinate/propylene glycol (40:60) solution. The concentration-time curve of R406 revealed a rapid absorption phase (tmax: 1.1–1.5 h) and a bi-phase decline in plasma concentrations (terminal elimination half-life [t1/2]: 12.9–20.9 h) [53]. The systemic exposure (Cmax and AUC0→∞) linearly increased when the dose ranged from 80 to 400 mg, although the exposure was essentially unchanged from 400-mg to 600-mg doses [53]. Second, they conducted a single oral dose study (80, 250, and 400 mg) and multiple repeated-dose studies (160 mg twice daily) of fostamatinib suspension. After administration, the R406 concentration reached a peak within 1–2 h, which was consistent with the results of R406 oral administration, indicating that fostamatinib was rapidly hydrolyzed and absorbed into the blood (Fig. 4) [53]. The linearity of R406 systemic exposure was observed only in the range of 80–250 mg of the fostamatinib dosage but not in 400 mg [53]. These results indicated that there was saturation of R406 absorption into the systemic circulation. Therefore, the initial dose of fostamatinib is set at between 100 and 250 mg in a clinical trial. Given that the active moiety, R406, and its N-glucuronide have existed in the intestinal tract, the possibility of entero-hepatic cycling and its effect on systemic circulation should be considered. Contrary to this expectation, the apparent secondary peak was not observed in the PK profile after fostamatinib oral administration in any phase I PK study (Fig. 4).

Fig. 4figure 4

Republished with permission of John Wiley & Sons [53]; permission conveyed through Copyright Clearance Center, Inc.

Plasma R406 concentration after a single oral administration of fostamatinib. Plasma R406 concentrations (ng/mL) in healthy human volunteers after an oral administration of a single dose of 80 mg, 250 mg, and 400 mg of fostamatinib in phase I clinical trial. Blood samples were collected at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 48, 56, 72, 96, and 120 h after dosing.

Absolute bioavailability was estimated at 55% according to the results of oral administration of fostamatinib 150 mg and intravenous administration of R406 100 µg. In this micro-dose intravenous study, t1/2 and clearance were 15.3 h and 15.7 L/h, respectively. These parameters were consistent with those in the dose-ascending trial and might suggest that saturation has not occurred in the metabolism and excretion in clinical doses of fostamatinib.

After repeated administration of fostamatinib 160 mg BID in healthy volunteers, an approximately 2-fold to 2.5-fold increase of R406 exposure was observed at day 7 as shown in Table 1, and fostamatinib achieved steady state following 3–4 days of administration BID [53]. As fostamatinib has been investigated for the treatment of RA, PK parameters of R406 were confirmed in patients who had stable disease with a weekly MTX regimen [60]. The PK parameters are shown in Table 1 and the data obtained from the patients were comparable to those from healthy volunteers [60].

PK Profiles in Special Populations

A phase I open-label clinical trial was performed to investigate the effect of renal or hepatic impairment on the R406 PK parameters [57]. Specifically, the criterion for renal function was determined by a creatinine clearance (mL/min) scale and dialysis requirements. The enrolled patients were divided into three groups (normal; 80 ≤ creatinine clearance, moderate; 30 ≤ creatinine clearance < 50, end-stage kidney disease; requiring hemodialysis). The results of the R406 PK parameters after a single oral dose of fostamatinib 150 mg are shown in Table 1. Each parameter indicated that fostamatinib could be administered regardless of the extent of renal impairment and the timing of hemodialysis in patients with end-stage kidney disease [57].

In addition, the criterion for hepatic impairment was determined based on the Child-Pugh score system, and the patients were divided into four groups (no hepatic impairment, mild; class A, moderate; class B, severe; class C). As hepatic metabolism by CYP3A4 and UGT1A9 is involved in the R406 pharmacokinetics [48], hepatic impairment could have a significant effect on its blood concentration; however, the PK parameters of R406 were consistent regardless of hepatic function, as shown in Table 1. Moreover, hypoalbuminemia due to hepatic impairment could influence the protein-binding rate, and unbound R406 concentration was also evaluated at 1, 6, and 24 h after fostamatinib administration. At all sampling times, the geometric mean of the unbound R406 ratio was the highest (60%) in the group with severe hepatic impairment compared with healthy patients [57]. Increased unbound drug concentrations could lead to individual differences in therapeutic efficacy and the incidence of AEs. Further analysis based on accumulated experience in clinical use to special populations is needed.

Drug–Drug Interactions

Several studies have examined the influence of drug–drug interactions of fostamatinib, and the results are summarized in Tables 2 and 3. As R406 is metabolized by CYP3A4 [48], CYP3A4 inhibitors or inducers may affect the R406 PK parameters. Martin et al. performed clinical studies of drug–drug interactions between fostamatinib and the CYP3A4 modulator ketoconazole (a potent inhibitor), verapamil (a moderate inhibitor), and rifampicin (an inducer) [58]. The co-administration of ketoconazole increased the R406 plasma concentration (Cmax and area under the plasma concentration–time curve [AUC]) and prolonged tmax and t1/2 [58]. Verapamil also increased AUC and t1/2, whereas there was no consistent effect on Cmax and tmax [58]. The co-administration of rifampicin was associated with a reduction of approximately 75% in AUC and 60% in Cmax of R406 [58]. CYP3A4 is also involved in the metabolism of oral contraceptives, especially ethinylestradiol. Concomitant dosage of fostamatinib and oral contraceptives significantly increased the Cmax and AUC of ethinylestradiol by 34.7% and 28.2%, respectively [61]. In addition, PK and PD interactions between fostamatinib and warfarin, an anticoagulant, were also reported in healthy volunteers [61]. Warfarin is a racemic mixture comprising equal proportions of S-warfarin and R-warfarin. CYP2C9 is responsible for the metabolism of S-warfarin, while R-warfarin is metabolized to inactive hydroxylated compounds by CYP1A2, CYP2C19, and CYP3A4 [62, 63]. Fostamatinib increased the systemic exposure to R-warfarin by 17.8%, whereas there was no difference in Cmax. These small fluctuations in warfarin pharmacokinetics did not translate into changes in the prothrombin time-international normalized ratio as a PD marker until 168 h post-dose [61].

Table 2 Drug–drug interactions affected by R406 exposureTable 3 Effect of fostamatinib drug–drug interactions on co-administered drugs

For evaluating R406 as a CYP inducer, an in vitro assay was performed using human hepatocytes [64]. R406 (3 µM and 10 µM) induced CYP2C8 to 52.8% and 74.7%, respectively, of the level achieved by rifampicin as a positive control, whereas R406 had minor effects on other CYP subtypes such as CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5. Therefore, a clinical trial was carried out to evaluate the influence of fostamatinib on the pharmacokinetics of pioglitazone, which is a potent CYP2C8 substrate [64]. Consequently, there were relatively small differences in the AUC of pioglitazone and its metabolite hydroxy pioglitazone, regardless of the co-administration of fostamatinib. These results suggest that fostamatinib is unlikely to have a clinically significant effect on pioglitazone, and the result could potentially be extrapolated to other CYP2C8 substrates [64].

As pH changes in the gastrointestinal tract could affect bioavailability, the effect of ranitidine, an H2 blocker, on the pharmacokinetics of fostamatinib was evaluated [49]. Ranitidine decreased R406 AUC and Cmax by less than 5% and had modest effects on R406 exposure [49].

Several studies reported drug–drug interactions via transporters related to fostamatinib and R406. An in vitro assay showed that fostamatinib was determined to be an inhibitor of digoxin, a P-gp substrate drug (IC50 = 3.2 μM), whereas R406 did not show inhibitory activity even at the highest soluble concentration [52]. As fostamatinib did not appear in blood plasma, inhibiting intestinal P-gp by fostamatinib could cause a drug–drug interaction. The ratio of the theoretical intestinal concentration (I2) and IC50 can be used to estimate whether there could be a drug–drug interaction related to transporter inhibition in the intestine [65]. Intestinal concentration/IC50 of P-gp after fostamatinib 100 mg was approximately 216 (I2 = 691 μM, fostamatinib molecular weight = 578.52) [52, 66]. Drug interaction guidance from the FDA suggested that there exists a potential for a drug–drug interaction if [I2]/IC50 is >10; thus, considerable attention should be paid when fostamatinib is co-administered with P-gp substrates [65]. When digoxin, a substrate of P-gp, was co-administered with fostamatinib, the digoxin geometric mean AUC and Cmax increased by 36.6% and 65.2%, respectively, although there were no serious AEs due to elevated exposure [52].

R406 also inhibited OATP1B1-mediated probe substrate ([3H] estradiol glucuronide) uptake, but the IC50 was greater than 10 μM. It had no effect on the probe substrate ([3H] methotrexate) uptake via OAT3 [66] and did not inhibit MRP2, OAT1, or OCT2 [54].

Moreover, both fostamatinib and R406 strongly inhibited the BCRP-mediated transport of estrone 3-sulfate, with IC50 values of 0.050 and 0.031 μM, respectively [66]. Compared with those of other drugs known to have BCRP inhibition, the IC50 values of fostamatinib and R406 against estrone 3-sulfate were equivalent or much stronger than those of eltrombopag (0.04 µM), imatinib (0.4 µM), sulfasalazine (0.56 µM), and cyclosporine (6.7 µM) [66,67,68]. Intestinal concentration/IC50 of BCRP in orally administered fostamatinib 100 mg was 13,820 [52, 66]. As this value was considerably higher than that of eltrombopag (75-mg dose, 323), clopidogrel (75-mg dose, 15; 300-mg dose, 59), and ezetimibe (10-mg dose, 34), significant attention should be paid when fostamatinib is co-administered with known BCRP substrates, such as ciprofloxacin, acyclovir, cimetidine, and especially statins [65, 66]. Martin et al. investigated the effects of fostamatinib on the pharmacokinetics of rosuvastatin and simvastatin in healthy subjects. The results showed that fostamatinib increased the AUC and Cmax of rosuvastatin by 95.6% and 88.4%, respectively, and those of simvastatin by 64.1% and 112.5%, respectively [

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