Pharmacokinetics of tacrolimus following an overdose in a patient with extreme obesity and genotype CYP3A5*3/*3: a case report

Abstract

This case involved a 27-year-old man with extreme obesity (body mass index 45.6 kg/m²) who had a history of fulminant hepatitis and living-donor liver transplantation at 11 years of age. He had been receiving oral sustained-release tacrolimus (TAC) 1.5 mg daily, and the trough concentration in the blood was below 2.0 ng/mL. He has an intrinsic cytochrome P450 3A5 (CYP3A5)*3/*3 (G/G) genotype and graft liver with CYP3A5*3 allele donated by his biological father. Additionally, there were no data on the phenotype of P-glycoprotein. He did not take medications, grapefruit, or St. John’s wort, which interact with CYP3A4 and P-glycoprotein. He intentionally took 30 mg of TAC and presented with symptoms of general malaise and poisoning. On the day of hospitalization (day 0), TAC was discontinued due to an elevated blood TAC concentration of > 60 ng/mL. Additionally, the blood TAC concentration exceeded 10 ng/mL for more than 3 days. He exhibited mild elevation of alanine aminotransferase, aspartate aminotransferase, and creatinine phosphokinase without apparent clinical symptoms. After discharge, blood TAC concentration decreased to 7.4 and 3.7 ng/mL on days 14 and 28, respectively, from the day of excessive TAC intake. Finally, the blood TAC concentration fell below 2.0 ng/mL on day 66. This case report showed that extreme obesity and the liver CYP3A5*3 allele delayed the elimination of TAC after excessive intake of the drug.

INTRODUCTION

Tacrolimus (TAC) inhibits the nuclear translocation of transcription factors that suppress T cell activation, resulting in immunosuppressive action, which is widely used in organ transplantation (e.g., kidney and liver) (Ekberg et al., 2007; TruneČka et al., 2015). The pharmacokinetics of TAC vary greatly depending on the body size, single nucleotide polymorphisms of cytochrome P4503A5 (CYP3A5), and concomitant medications at therapeutic doses (Andrews et al., 2019; Passey et al., 2011). Overexposure to TAC following long-term administration could result in various adverse effects such as nephrotoxicity, hypertension, and diabetes mellitus, which are concentration-dependent (Murray et al., 2013). Generally, therapeutic drug monitoring helps in optimizing TAC doses and improving the net clinical benefit (Brunet et al., 2019).

Several case reports have described excessive intake of TAC, but did not focus on body size and single nucleotide polymorphisms of CYP3A5 in liver transplantation (Mrvos et al., 1997; Tseng et al., 2020; Su et al., 2002). In this case report, we showed delayed elimination of TAC after an overdose of 30 mg of oral TAC in a liver transplant patient who had extreme obesity (≥ 40.0 kg/m²) (Jensen et al., 2014) and intrinsic CYP3A5*3/*3 (G/G), namely, the non-expressor phenotype.

Case report

A 27-year-old male (170.3 cm, 132.3 kg, and body mass index [BMI] 45.6 kg/m²) had a history of fulminant hepatitis from unknown causes, which was treated by living-donor liver transplantation at the age of 11 years. He had an intrinsic CYP3A5*3/*3 (G/G) genotype and graft liver (unknown CYP3A5 genotype) that was donated by his biological father. He was receiving TAC monotherapy for 8 years without a rejection episode. His outpatient prescriptions included sustained-release TAC (Graceptor Capsules, Astellas Pharma Inc., Tokyo, Japan) 1.5 mg daily at 9:00 without other medications that interact with CYP3A4 and P-glycoprotein (e.g., azole antifungals and certain calcium channel blockers). Additionally, he did not take grapefruit and St. John’s wort, which interact with TAC for several days. There were no problems with medication adherence. TAC trough concentration in the whole blood was less than 2.0 ng/mL in the previous 6 months, which is below the detection limit. He intentionally consumed an excessive dose of 30 mg of sustained-release TAC (day 0, 7:00), leading to general malaise. He was then transported to Mie University Hospital by ambulance 3 hr after overdose intake.

Initial management involved administration of intravenous fluids (500 mL Ringer’s solution) and activated charcoal (50 g). Chest radiography and whole-body computed tomography did not reveal any abnormalities. There were no abnormal laboratory findings except for mild elevation of C-reactive protein and white blood cell counts without fever (Table 1). Vital signs were stable throughout all clinical courses.

Table 1. Time-courses of clinical laboratory data.

	D-2 10:00	D0 11:00	D0 15:00	D1 7:00	D2 7:00	D3 7:00	D4 7:00	D5a 7:00	D14 10:00	D28 10:00	D66 10:00
ALT, IU/L	37	35	35	39	36	46	47	-	27	41	30
AST, IU/L	27	25	34	30	27	35	32	-	21	30	21
CPK, IU/L	147	170	297	734	730	514	241	-	128	194	124
CRP, mg/dL	2.00	2.93	-	2.97	3.94	3.45	3.42	-	1.87	2.96	2.44
WBC, × 103/µL	12.00	10.80	11.68	11.39	10.38	11.32	11.26	-	11.19	10.78	10.99

Abbreviations: D, day; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CRP, C-reactive protein; WBC, white blood cell

He intentionally overdosed by consuming 30 mg of sustained-release tacrolimus on day 0 at 7:00.

a: He restarted 1.5 mg of sustained-release tacrolimus daily from day 5 (9:00) onwards.

The time course of TAC concentration during hospitalization is presented in Fig. 1. TAC concentration was > 60.0 ng/mL 4 hr after overdose intake. The blood TAC concentration decreased to 50.7 ng/mL 8 hr after overdose intake, and then gradually decreased from day 1 to day 4. On day 5, the patient restarted TAC monotherapy although the trough concentration was not measured. No significant nephrotoxicity or central nervous system toxicity was observed during hospitalization. Additionally, he did not experience hematological disorders such as anemia in this period. However, clinical laboratory data revealed a slight elevation in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine phosphokinase (CPK) levels without clinical symptoms (Table 1). Since the general condition during hospitalization was uneventful, the patient was discharged from the hospital.

Fig. 1

Time course of the concentration of tacrolimus in the acute stage following overdose. The x-axis and y-axis represent the time after overdose and tacrolimus concentration, respectively. Each closed circle represents tacrolimus concentrations and actual values are indicated near the corresponding circle. Blood tacrolimus concentration is measured using the chemiluminescent immunoassay method (Abbott Japan LLC, Tokyo, Japan). The calibration ranges from 0.0 to 30.0 ng/mL with a quantitation limit of 2.0 ng/mL. The calculated plasma half-life of tacrolimus using two sampling points (22.7 ng/mL and 9.8 ng/mL) is roughly 60 hr. The half-life of tacrolimus in a clinical trial is approximately 16 hr in liver transplant patients (the interview form for Graceptor capsule ver.19 (in Japanese), Astellas Pharma Ltd. accessed on 3 September 2021).

After discharge, clinical laboratory data revealed an improvement in ALT, AST, and CPK levels. Furthermore, there was a significant decline in TAC concentration to 7.4 and 3.7 ng/mL on days 14 and 28, respectively. Interestingly, it took about 2 months (day 66) for the TAC concentration to decrease to < 2.0 ng/mL, which is comparable to the level before hospitalization.

DISCUSSION

This case report demonstrated delayed the elimination of TAC following an overdose of 30 mg TAC in a patient with extreme obesity and intrinsic CYP3A5*3/*3 (non-expressor), suggesting that close monitoring of blood TAC concentration is necessary to assess the delay in TAC elimination from the blood.

The TAC concentration exhibited a biphasic time-concentration profile during observation. A previous report has indicated that the peak concentration of TAC is 26.53 ng/mL at a single oral dose of 10 mg (the interview form for Graceptor capsule ver.19 (in Japanese), Astellas Pharma Ltd. accessed on 3 September 2021). Therefore, we calculated the TAC concentration to be approximately 80 ng/mL 4 hr after intake by considering the proportion. Notably, it is conceivable that TAC elimination was delayed after day 1. The plasma half-life of TAC from day 1 to day 4 was calculated to be approximately 60 hr. The plasma half-life in the patient was markedly longer than the half-life at about 16 hr calculated using peak and trough concentration data (14.1 ng/mL and 5.8 ng/mL, respectively) of liver transplant patients, which was obtained from the interview form of this drug (the interview form for Graceptor capsule ver.19 (in Japanese), Astellas Pharma Ltd. accessed on 3 September 2021). This prolongation of half-life was considered to be attributed not only to the CYP3A5 genotype but also to BMI because the reported TAC clearance in patients with CYP3A5*3/*3 was only about half of that in the wild type (Andrews et al., 2019). Extreme obesity and the presence of liver CYP3A5*3 alleles, which were donated by the patient’s biological father might be responsible for the delayed TAC pharmacokinetics in the late phase. Since the present case has the CYP3A5*3/*3 genotype, it is clear that his donor (his biological father) possesses either the CYP3A5*1/*3 or *3/*3 genotype.

Obesity generally influences the pharmacokinetics of a drug. For instance, the systemic clearance of CYP3A4 substrates was reported to be low in obese patients (Brill et al., 2012). Additionally, interleukin-6 was reported to suppress the expression of CYP3A4 in vitro (Krogstad et al., 2021), suggesting that obese patients exhibiting potential inflammation could influence CYP3A4 activity. Furthermore, there was another point to note that obesity could affect volume distribution of TAC because the information of this drug described that the coefficient of octanol-water partition exceeds 1000, and TAC can be well distributed throughout the adipose tissue (the interview form for Graceptor capsule ver.19 (in Japanese), Astellas Pharma Ltd. accessed on 3 September 2021). A previous study has demonstrated that the obesity group had higher TAC concentrations than the normal body size group when therapeutic doses were administered (Han et al., 2012). Interestingly, BMI affected TAC exposure in each CYP3A5 genotype differently, and TAC trough concentration was positively correlated with BMI in the CYP3A5*3/*3 groups (Andrews et al., 2017). Similarly, our patient experienced a delay in TAC elimination during observation. Therefore, obesity may have led to increased TAC concentration in the blood.

Several case reports have demonstrated that TAC concentrations after overdose intake return to the normal range within a few days as shown in Table 2 (Mrvos et al., 1997; Hardwick and Batiuk, 2002; Tseng et al., 2020). Notably, the high blood TAC concentration became persistent for approximately 2 months in this case. In the light of pharmacokinetics, CYP3A5 and P-glycoprotein play an important role in determining TAC exposure in transplant patients (Sikma et al., 2015). The phenotype of CYP3A5 in recipients and donors apparently influences the pharmacokinetics of TAC (Debette-Gratien et al., 2016). Conversely, ABCB1, which encodes P-glycoprotein, had a less significant impact on TAC exposure than CYP3A5 (Miyata et al., 2016). Although acute inflammation such as sepsis has been reported to affect TAC clearance, resulting in high blood concentration (Bonneville et al., 2020), the patient maintained a mild elevation in C-reactive protein level even before the overdose. Furthermore, it has been reported that hematocrit influences TAC exposure (Størset et al., 2014); however, hematocrit (about 40%) did not change significantly during observation. Therefore, we consider that liver CYP3A5 activity and obesity contributed to the delay in TAC elimination in this case.

Table 2. Summary of case reports.

	Sex	Age, y	BW, kg	Ingestion TAC dose, mg	Maximum TAC concentration, ng/mL	Time required for maximum TAC concentration to reach normal TAC concentration, day
1	F	2	11.3	10	-	-
2	F	2	11	11	-	-
3	M	29	60	90	8.5	1
4	F	23	53.6	375	11.4	6
5	F	34	-	7–9 (0.25 mg/kg)	-	-
6	M	59	79	5a	118.5	6
7	F	33	-	-	21.4	-

Abbreviations: y, years; TAC, tacrolimus; BW, body weight; M, male; F, female

We summarized case reports in Table 2 (Mrvos et al., 1997; Hardwick and Batiuk, 2002; Tseng et al., 2020).

a: He received a twice-daily dose of 5 mg tacrolimus for 8 days.

In summary, this case suggests that obesity and liver CYP3A5 activity can interfere with TAC pharmacokinetics. Clinicians should consider the underlying pharmacokinetic features of TAC when monitoring TAC therapy. In patients requiring long-term treatment with TAC, it would be better to assess the genotype of CYP3A5 to understand the risk of delayed TAC pharmacokinetics.

Conflict of interest

The authors declare that there is no conflict of interest.

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