2024 FDA-Approved Drug Highlights: Overview of Human Pharmacokinetics and DDI Profiles

In 2024, the U.S. Food and Drug Administration (FDA) approved 50 new small-molecule and biologic drugs, spanning diverse therapeutic areas and molecular classes^[1]. This article analyzes 12 representative drugs, focusing on their drug metabolism and pharmacokinetics (DMPK) and drug interaction (DDI) characteristics. Highlighted therapies include Rezdiffra (resmetirom, the first drug approved for non-alcoholic steatohepatitis [NASH]/metabolic dysfunction-associated steatohepatitis [MASH]), Lazcluze (lazertinib, for EGFR-mutant non-small cell lung cancer), Cobenfy (xanomeline/trospium chloride, for schizophrenia), Alyftrek (vanzacaftor/tezacaftor/deutivacaftor, for cystic fibrosis), and Winrevair (sotatercept-csrk, for pulmonary arterial hypertension). This review provides pharmacokinetic data and underscores clinical implications across molecular types and indications.

Overview of 2024 FDA-approved drugs

The FDA’s Center for Drug Evaluation and Research (CDER) approved 50 new drugs in 2024 (Click to access the full detailed list: Summary of Human ADME Data for 50 FDA-Approved Drugs in 2024.), slightly fewer than 2023’s 55 approvals but exceeding the 10-year rolling average of 46.5.

Key statistics:

• Priority review: 56%

• Orphan drug designation: 52%

• Breakthrough therapy designation: 36%

• Accelerated approval (surrogate endpoints): 14%

  
  

1. Molecular diversity (Figure 1):

• Small molecules: 60% (30 drugs), predominantly oncology agents (23%).

• Biologics: 32% (16 drugs), including 13 monoclonal/bispecific antibodies (e.g., tislelizumab-jsgr from BeiGene).

• TIDES: 4 drugs (2 oligonucleotides, 2 peptides).

• PEGylated/deuterated drugs: 4 drugs (2 deuterated small molecules, 2 PEGylated peptides).

• Fluorinated/N-aromatic heterocycles: 66% of small molecules.

2. Therapeutic areas (Table 1, Figure 2):

• Oncology: 14 drugs (7 small molecules, 6 antibodies, 1 cytokine fusion protein).

• Cardiovascular: 4 drugs (3 small molecules, 1 antisense oligonucleotide).

• Central nervous system: 2 drugs.

• Rare diseases: e.g., Alyftrek (cystic fibrosis), Tryngolza (familial chylomicronemia syndrome).

Figure 1. Number of FDA-approved drugs in 2024 by molecular type

Table 1. Number of FDA-approved drugs in 2024 by disease area

Figure 2. FDA-Approved drugs by molecular type and disease area

Overall, the FDA’s drug approvals in 2024 highlight the importance of biologics, TIDES drugs, fluorinated compounds, and N-heterocyclic compounds in drug development, as well as the ongoing development of combination therapies and imaging diagnostic drugs.

Detailed pharmacokinetic and DDI profiles of 12 FDA-approved drugs

Lazcluze™ (lazertinib)

Pharmacokinetics & drug interactions:

Absorption:

• Dose-proportional increases in C_max and AUC from 20 mg to 320 mg (0.08–1.3x the approved dose).

• Steady-state plasma exposure achieved by Day 15 (AUC accumulation ratio: 2x).

• T_max: 2–4 hours.

Distribution:

• Volume of distribution (V_d): 2680 L (51% CV).

• Plasma protein binding: 99.2%.

Metabolism:

• Half-life (t_½): 3.7 days (56% CV).

• Clearance (CL): 36.4 L/h (47% CV).

• Primarily metabolized via glutathione conjugation and CYP3A4.

Excretion:

• Feces: 86% (≤5% unchanged).

• Urine: 4% (≤0.2% unchanged).

Drug interactions:

• Inhibits CYP3A4, UGT1A1, BCRP, and OCT1 in vitro.

• Strong CYP3A4 inducers (e.g., rifampin): ↓C_max by 72%, ↓AUC by 83%.

• Strong CYP3A4 inhibitors (e.g., itraconazole): ↑C_max by 1.2x, ↑AUC by 1.5x.

• CYP3A4 substrates (e.g., midazolam): ↑Midazolam C_max by 1.4x, AUC by 1.5x.

• BCRP substrates (e.g., rosuvastatin): ↑Rosuvastatin C_max by 2.2x, AUC by 2x.

Cobenfy™ (xanomeline + trospium chloride)

Pharmacokinetics & drug interactions:

Absorption:

• Xanomeline:

  T_max: 2 hours.

  High-fat meal ↑AUC by 30% (no change in C_max).

• Trospium chloride:

  T_max: 1 hour.

  High/low-fat meals ↓AUC by 85–90%, ↓C_max by 70–75%.

Distribution:

• Xanomeline: V_d = 10,800 L; plasma protein binding = 95%.

• Trospium chloride: V_d = 531 L; plasma protein binding = 80%.

Metabolism:

• Xanomeline:

  t_½: 5 hours.

  CL: 1950 L/h.

  Metabolized by CYP2D6, CYP2B6, CYP1A2, CYP2C9/19, and FMO1/3.

• Trospium chloride:

  t_½: 6 hours.

  CL: 796 L/h.

  Metabolized via ester hydrolysis and glucuronidation.

Excretion:

• Xanomeline: Urine (78%, <0.01% unchanged); feces (12%).

• Trospium chloride: Urine (85–90% unchanged).

Drug interactions:

• Risk of increased adverse effects with CYP2D6 inhibitors, sensitive substrates of CYP3A4 or P-gp, or drugs eliminated via active renal tubular secretion.

Alyftrek™ (vanzacaftor + tezacaftor + deutivacaftor)

Pharmacokinetics & drug interactions:

Absorption (12+ years):

• Vanzacaftor:

  C_max,ss: 0.812 μg/mL; AUC_0-24h,ss: 18.6 μg·h/mL.

  T_max: 7.8 hours (3.7–11.9 hours).

  Food effect: ↑AUC by 4x (low-fat meals), 6x (high-fat meals).

• Tezacaftor:

  C_max,ss: 6.77 μg/mL; AUC_0-24h,ss: 89.5 μg·h/mL.

  T_max: 1.6 hours (1.4–1.7 hours).

• Deutivacaftor:

  C_max,ss: 2.33 μg/mL; AUC_0-24h,ss: 39.0 μg·h/mL.

  T_max: 3.7 hours (2.7–11.4 hours).

  Food effect: ↑AUC by 3x (low-fat meals), 4x (high-fat meals).

Distribution:

• Vanzacaftor: V_d = 121 L; plasma protein binding >99%.

• Tezacaftor: V_d = 73.1 L; plasma protein binding ~99%.

• Deutivacaftor: V_d = 159 L; plasma protein binding >99%.

Metabolism:

• All three components were metabolized by CYP3A4/5.

• Vanzacaftor: t_½ = 92.8 hours; CL = 1.34 L/h.

• Tezacaftor: t_½ = 22.5 hours; CL = 1.22 L/h.

• Deutivacaftor: t_½ = 19.2 hours; CL = 7.29 L/h.

Excretion:

• Vanzacaftor: Feces (91.6%, metabolites); urine (0.5%).

• Tezacaftor: Feces (72%); urine (13.7%).

Drug interactions:

• In vitro, vanzacaftor is a substrate of CYP3A, and inhibits BCRP and P-gp; Tezacaftor is a substrate of CYP3A, P-gp, BCRP and OATP1B1, and inhibits P-gp; Deutivacaftor is a substrate of CYP3A and P-gp, and inhibits CYP2C8/2C9/3A4, P-gp and BCRP.

• Avoid strong/moderate CYP3A4 inducers (↓efficacy) or inhibitors (↑toxicity).

Rezdiffra™ (resmetirom)

Pharmacokinetics & drug interactions:

Absorption:

• Steady state achieved in 3–6 days.

• 80 mg/day: C_max,ss = 778 ng/mL (41.5% CV); AUC_tau,ss = 5850 ng·h/mL (60.5% CV).

• 100 mg/day: C_max,ss = 971 ng/mL (40.9% CV); AUC_tau,ss = 7780 ng·h/mL (65.5% CV).

• Food reduces C_max by 33% and delays T_max by 2 hours.

Distribution: V_d = 68 L (227% CV); plasma protein binding >99%.

Metabolism:

• t_½ = 4.5 hours; CL = 17.5 L/h (56.3% CV).

• Metabolized by CYP2C8.

Excretion: Feces (67%); urine (24%).

Drug interactions:

• Inhibits CYP2C8, UGT1A4/1A9, OATP1B1/1B3, BCRP, OAT3, and BSEP in vitro.

• A substrate of OATP1B1/1B3 and BCRP in vitro.

• Clopidogrel (CYP2C8 inhibitor): ↑Resmetirom AUC by 1.7x.

• Piogkitazone (CYP2C8 substrate): ↑Piogkitazone AUC by 1.5x.

• Statins (e.g., simvastatin): ↑Simvastatin AUC by 1.7x.

Voranigo™ (vorasidenib)

Pharmacokinetics & drug interactions:

Absorption:

• Dose-proportional exposure (10–200 mg).

• At the highest approved recommended dosage (50 mg/day): C_max= 133 ng/mL (73% CV); AUC = 1988 h·ng/mL (95% CV).

• T_max: 2 hours (0.5–4 hours).

• Absolute bioavailability: 34%.

• Food effect: High-fat and high-calorie meal ↑C_max by 3.1x, AUC by 1.4x.

        Low-fat and low-calorie meal ↑C_max by 2.3x, AUC by 1.4x

Distribution:

• V_d = 3930 L (40% CV); human plasma protein binding = 97%.

• Brain tumor-to-plasma ratio: 1.6.

Metabolism:

• t_½ = 10 days (57% CV); CL = 14 L/h (56% CV).

• Primarily metabolized by CYP1A2; non-CYP pathways account for 30%.

Excretion: Feces: 85% (56% unchanged); urine: 4.5%.

Drug interactions:

• Vorasidenib is an inducer of CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A and UGT1A4.

• Vorasidenib is an inhibitor of BCRP.

• Concomitant use with moderate CYP1A2 inhibitors (e.g., ciprofloxacin): ↑ C_max 1.3x, ↑AUC 2.5x.

• Concomitant use with strong CYP1A2 inhibitors (e.g., fluvoxamine): ↑AUC ≥5x.

• Concomitant use with moderate CYP1A2 inducers (e.g., phenytoin or rifampicin): ↓C_max 30%, ↓AUC 40%.

Tryvio™ (aprocitentan)

Pharmacokinetics & drug interactions:

Absorption:

• Single 25 mg dose: C_max = 1.3 μg/mL (19% CV), T_max = 4–5 hours, AUC_0-tau=23 μg·h/mL (17% CV);

• Steady state achieved by Day 8 (accumulation ratio: 3x).

Distribution:

• V_d = 20 L; plasma protein binding >99%.

• Whole blood-to-plasma ratio: 0.63.

Metabolism:

• t_½ = 41 hours; CL = 0.3 L/h.

• Metabolized by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis

Excretion: Feces (25%, 6.8% unchanged); urine (52%, 0.2% unchanged).

Drug interactions:

• Inhibits CYP3A4, CYP2C family, BCRP, BSEP, and NTCP.

• Inducer of CYP3A4

• Substrate and inhibitor of UGT1A1 and UGT2B7.

• Substrate of P-gp and BCRP

• Concomitant administration with UGT inducers: ↓aprocitentan exposure.

Rytelo™ (imetelstat)

Pharmacokinetics & drug interactions:

Absorption:

• 7.1 mg/kg dose every 4 weeks: C_max = 18.3 μM (27.3% CV); AUC_0-28d = 114.2 h·μM (43.2% CV).

• No accumulation after 4-week cycles.

Distribution:

• V_d = 14.1 L (27.2% CV); human plasma protein binding >94%.

Metabolism:

• t_½ = 4.9 hours (43.2% CV).

• Metabolized by nucleases to nucleotides of various lengths.

Excretion: Data not provided.

Drug interactions:

• Inhibits OATP1B1 and OATP1B3; not an inhibitor or inducer of CYP450 enzymes.

Tryngolza™ (olezarsen)

Pharmacokinetics & drug interactions:

Absorption:

• 80 mg/month: C_max = 883 ng/mL (SD 662); AUC_τ = 7440 ng·h/mL (SD 3880).

• T_max: 2 hours; no accumulation.

Distribution:

• V_d (central) = 91.9 L; V_d (peripheral) = 2960 L.

• plasma protein binding>99%

• Primarily distributed to the liver and kidneys.

Metabolism:

• t_½: ~4 weeks.

• metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.

Excretion: Urine (<1% unchanged within 24 hours).

Drug interactions:

• No interactions with CYP450, transporters, or plasma proteins.

Tevimbra™ (tislelizumab-jsgr)

Pharmacokinetics:

Absorption:

• 200 mg every 3 weeks: C_max = 110 μg/mL (22.2% CV); AUC_tau = 1283 μg·d/mL (28.7% CV).

• Steady state achieved by Week 12 (accumulation ratio: 2.14x).

Distribution: V_d = 6.42 L (32.6% CV).

Metabolism:

• t_½ = 24 days (31% CV); CL = 0.153 L/day (29.5% CV).

• Degraded via proteolysis (similar to endogenous IgG).

Excretion: Data not provided.

Drug interactions: Data not provided.

Kisunla™ (donanemab-azbt)

Pharmacokinetics:

Absorption:

• Dose: 700 mg → 1400 mg every 4 weeks.

• Steady state reached after first dose (accumulation <1.3x).

• Dose-proportional exposure (10–40 mg/kg).

Distribution: V_d (central) = 3.36 L.

Metabolism:

• t_½ = 12.1 days; CL = 0.0255 L/h.

• Degraded via proteolysis.

Excretion: Negligible renal elimination.

Drug interactions: Data not provided.

Imdelltra™ (tarlatamab-dlle)

Pharmacokinetics & drug interactions:

Absorption:

• Dose-proportional exposure (1–100 mg every 2 weeks).

• Steady state (Cycle 2 Day 15): C_avg = 1040 ng/mL (44% CV); C_max = 3400 ng/mL (40% CV).

Distribution: V_d = 8.6 L (18.3% CV).

Metabolism:

• t_½ = 11.2 days (4.3–26.5 days); CL = 0.65 L/day (44% CV).

• Degraded into small peptides.

Excretion: Data not provided.

Drug interactions:

• May transiently inhibit CYP450 enzymes due to cytokine release.

Winrevair™ (sotatercept-csrk)

*The projected sales in the images are sourced from reference 6.

Pharmacokinetics:

Absorption:

• 0.7 mg/kg every 3 weeks: AUC = 172 μg·d/mL (34.2% CV); C_max = 9.7 μg/mL (30% CV).

• Steady state achieved at ~15 weeks (accumulation ratio: 2.2x).

• Absolute bioavailability: 66%.

• T_max: 7 days.

Distribution: V_d = 5.3 L (27.3% CV); weight-dependent.

Metabolism:

• t_½ = 24 days; CL = 0.18 L/day (weight-dependent).

• Degraded into small peptides.

Excretion: Data not provided.

Drug interactions: Data not provided.

Concluding remarks

By analyzing the pharmacokinetic and DDI characteristics of representative new drugs approved by the FDA in 2024, it can be observed that drugs of different molecular types and indications exhibit distinct advantages in ADME studies. The significant optimization of these ADME and DDI properties provides valuable insights and references for future drug development.

WuXi AppTec DMPK leverages its extensive expertise across small molecules, antibodies, nucleic acids, and peptides, with specialization in ADME screening and optimization, accelerating client projects into clinical stages while proactively identifying and mitigating potential clinical risks.

Authors: Yan Pan, Yunyi Yan, Ting Peng, Yu Wang, Lijuan Hou, Jing Jin

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