Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters

Abstract

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.

Figure 1

Diagrams of hepatobiliary disposition of bilirubin (a) and the bilirubin submodel structure within DILIsym (b). CB, conjugated bilirubin; DJS, Dubin‐Johnson Syndrome; GS, Gilbert's Syndrome; HC, hepatocytes; MRP, multidrug resistance‐associated protein; OATP, organic anion transporting polypeptide; RBC, red blood cell; RS, Rotor Syndrome; UB, unconjugated bilirubin; UGT, UDP glucuronosyltransferase.

Figure 2

Simulated and observed bilirubin levels in patients with inherited disorders of bilirubin metabolism and transport. Top panels represent observed (closed circles)8, 11, 12, 13, 14, 27 and simulated (open circles) serum total bilirubin (TB) levels. Bottom panels represent observed (closed circles) and simulated (open circles) percent conjugated bilirubin (CB) in serum compared to serum TB. Multiple simulated individuals for each condition represent individuals with impaired enzyme/transporter function to a different extent within the ranges. Simulated patients have 70–95% impaired OATP1B1/1B3 function (Rotor Syndrome (RS)), 30–60% impaired UGT1A1 function (Gilbert's Syndrome (GS)), 70–90% impaired UGT1A1 function (Crigler‐Najjar Syndrome (CNS)), or 50–90% impaired MRP2 function (Dubin‐Johnson Syndrome (DJS)), respectively. Asterisks (*) represent less frequently observed serum TB ranges in patients with CNS or DJS.

Figure 3

Simulated and observed bilirubin levels in rats lacking Mrp2 or Ugt1a1, and mice lacking Ugt1a1. Closed and open circles represent observed and simulated serum total bilirubin (TB), respectively. (a) Observed data represent mean serum TB in Mrp2 knockout rats, EHBR rats, and TR^‐ rats (top to bottom).41, 46 Simulated rats have 50–100% impaired Mrp2 function. (b) Observed data represent mean serum TB in Ugt1a1 knockout rats obtained from multiple studies.39, 42, 43, 47 Simulated rats have 50–100% impaired Ugt1a1 function. (c) Observed data represent mean serum TB in Ugt1a1(‐/‐) (top) and Ugt1a1 (+/‐) mice (bottom).44 Simulated mice have 50–100% impaired Ugt1a1 function.

Figure 4

Simulated and observed bilirubin levels in mice lacking single or multiple transporters. Observed (closed bars)8 and simulated (open bars) serum total bilirubin (TB) (a), percent conjugated bilirubin (CB) in serum compared to serum TB (b), and biliary excretion of TB presented as percent of wildtype animals (c).

Figure 5

Indinavir‐mediated hyperbilirubinemia in normal patients and patients with Gilbert's syndrome (GS) administered 800 mg indinavir t.i.d. for 1 month. For the data reported by Rotger et al.,24 boxes represent 25th–75th percentile of the observed data, and whiskers represent the minimum and maximum observed data; serum total bilirubin (TB) levels in individuals with heterozygote and homozygote for GS alleles are presented separately. Zucker et al.23 reported individual TB levels, which are represented with closed circles; the whisker represents the median value. Simulated normal individuals have unimpaired UGT1A1 function, whereas simulated patients with GS have 40–60% impaired UGT1A1 function.

Figure 6

Simulated and observed peak serum total bilirubin (TB) levels in rats administered 50, 200, or 500 mg/kg chemokine receptor antagonist (CKA). (a) Maximum serum TB fold‐change from baseline for increasing doses of CKA. Black dots represent data from preclinical trials and red asterisks denote simulation results for SimPops (n = 294) with combined effects of hepatotoxicity and bilirubin transporter inhibition. (b) Maximum serum TB fold‐change from baseline for increasing doses of CKA simulated with combined effects of hepatotoxicity and bilirubin transporter inhibition, hepatotoxicity only, or bilirubin transporter inhibition only.