Identification of a pharmacokinetic interaction between teicoplanin and sulfo-butyl ether-beta-cyclodextrin, an excipient in the intravenous posaconazole formulation

This study identifies a pharmacokinetic interaction where the sulfo-butyl ether-beta-cyclodextrin (SBECD) excipient in intravenous posaconazole reduces teicoplanin protein binding, leading to increased renal elimination and lower drug concentrations in hematopoietic stem cell transplant patients.

The Gist

The Big Picture: A Case of "Too Many Cooks in the Kitchen"

Imagine a patient who has just undergone a major bone marrow transplant (like rebuilding a house from the ground up). Their immune system is weak, so they are vulnerable to infections. To protect them, doctors give them a "security team" of medicines:

1. Teicoplanin (TEIC): A powerful antibiotic to fight bacterial invaders.
2. Posaconazole (PSCZ): A strong antifungal to stop mold and yeast.

Usually, these two work fine together. But this study discovered a sneaky problem: when the antifungal is given through an IV drip, it accidentally steals the antibiotic's effectiveness.

The Culprit: The "Hidden Helper" (SBECD)

Here is the twist: The problem isn't the antifungal drug itself. It's a helper ingredient (an excipient) used to make the IV version of the antifungal dissolve in water. This helper is called SBECD.

Think of SBECD as a molecular "life raft" or a floating basket.

• The antifungal drug is oily and hates water (like a duck that refuses to swim).
• SBECD is a ring-shaped molecule with a hollow, oily center. It grabs the antifungal, holds it inside its "basket," and lets it float safely through the watery bloodstream.

The Accident: The Life Raft Steals the Passenger

The researchers found that this "life raft" (SBECD) is so good at its job that it gets confused. It doesn't just hold the antifungal; it also grabs onto the antibiotic (Teicoplanin) by mistake.

Here is how the interaction plays out, step-by-step:

1. The Normal Routine:
   Normally, Teicoplanin is like a VIP guest at a party. It likes to stick to Serum Albumin (a protein in your blood), which acts like a luxury limousine. Riding in the limo protects the drug, keeps it in the body longer, and lets it do its job fighting bacteria.

2. The Intrusion:
   When the patient gets the IV antifungal, the SBECD "life rafts" flood the bloodstream. These rafts are sticky and grab onto the Teicoplanin VIP.

3. The Switch:
   The Teicoplanin gets pulled out of the "luxury limo" (Serum Albumin) and shoved into the SBECD "life raft."

   • The Problem: The SBECD raft is small and unstable compared to the limo. It can't hold the drug securely in the body.

4. The Escape:
   Because the drug is now in the small raft instead of the limo, the kidneys (the body's trash collectors) see it as something that needs to be flushed out immediately.

   • Result: The Teicoplanin is peed out of the body much faster than usual.

The Evidence: What the Scientists Found

The researchers proved this story in three ways:

• In Humans (The Hospital Data): They looked at patients who had bone marrow transplants.

  • When patients took the antifungal as a pill, the antibiotic levels stayed normal. (Pills don't use the SBECD raft).
  • When patients took the antifungal as an IV drip, the antibiotic levels in their blood dropped by about 35%. The drug was vanishing too fast.

• In Rats (The Lab Test): They gave rats the IV antifungal and then the antibiotic.

  • The rats' blood levels of the antibiotic crashed.
  • The rats' urine levels of the antibiotic skyrocketed.
  • This confirmed that the drug was being flushed out by the kidneys.

• On the Computer (The Simulation): They used 3D modeling to see how the molecules fit together.

  • They saw that the "tail" of the antibiotic fits perfectly inside the hollow center of the SBECD ring. It's like a key fitting into a lock. This confirmed why they stick together.

Why Does This Matter?

This is a classic case of a Drug-Excipient Interaction.

• The Lesson: It's not just the active medicine that causes interactions; sometimes the "filler" ingredients (like the SBECD raft) cause the trouble.
• The Risk: If a doctor gives a patient the IV version of the antifungal without knowing this, the antibiotic might become too weak to kill the bacteria, leading to treatment failure.
• The Solution: Doctors might need to increase the dose of the antibiotic or switch to the pill version of the antifungal when treating these specific patients.

Summary Analogy

Imagine you are trying to keep a valuable painting (the antibiotic) safe in a museum (the body).

• Normal: The painting is on a heavy, secure pedestal (Serum Albumin). It stays put.
• The IV Antifungal: A delivery truck arrives with a bunch of bouncy, sticky foam blocks (SBECD).
• The Accident: The foam blocks accidentally grab the painting and wrap it up. Because the foam is light and bouncy, the painting is easily swept away by the wind (the kidneys) and lost before it can protect the museum.

The takeaway: When mixing medicines, always check the ingredients list, because sometimes the "boring" helpers are the ones causing the chaos!

Technical Summary

1. Problem Statement

Patients undergoing hematopoietic stem cell transplantation (HSCT) are highly susceptible to infections and frequently require concurrent therapy with multiple antibiotics and antifungals. Teicoplanin (TEIC), a glycopeptide antibiotic with a long half-life and high protein binding, is commonly used for Gram-positive infections in this population. Posaconazole (PSCZ), a potent azole antifungal, is often co-administered for fungal prophylaxis.

While PSCZ is known to inhibit CYP3A4 and P-glycoprotein (affecting drugs metabolized by these pathways), it is generally assumed to have minimal impact on renally excreted drugs like TEIC. However, the intravenous (i.v.) formulation of PSCZ contains a high concentration of sulfo-butyl ether-β-cyclodextrin (SBECD), a solubilizing excipient. The clinical problem addressed is the unexplained reduction in TEIC plasma concentrations observed when co-administered with i.v. PSCZ, potentially leading to subtherapeutic levels and treatment failure. The study aims to elucidate the mechanism behind this interaction, specifically investigating the role of the excipient SBECD.

2. Methodology

The study employed a multi-faceted approach combining clinical retrospective analysis, animal pharmacokinetics, molecular modeling, and in vitro assays:

• Clinical Retrospective Analysis:

  • Population: 8 HSCT patients at Kyoto University Hospital receiving TEIC and PSCZ (oral or i.v.) between 2020–2022.
  • Data: 83 trough TEIC plasma concentration measurements were analyzed under three conditions: no PSCZ, oral PSCZ, and i.v. PSCZ.
  • Statistical Model: A linear mixed-effects model was used to evaluate the association between PSCZ administration and TEIC concentration-to-dose (C/D) ratios, adjusting for covariates (age, sex, albumin, eGFR).

• Animal Pharmacokinetics (Rats):

  • Model: 8-week-old male Wistar rats.
  • Groups: Rats received saline, i.v. PSCZ (containing SBECD), or SBECD alone, followed by i.v. TEIC.
  • Measurements: Plasma and urine samples were collected over 120 minutes. TEIC components (A2-1, A2-2, A2-3, A2-4, A2-5, and hydrolysis product A3-1) were quantified using LC-MS/MS.
  • Endpoints: Area under the curve (AUC) and urinary excretion of total TEIC and specific components.

• Molecular Docking Simulation:

  • Target: Interaction between TEIC A2-2 (the major clinical component) and SBECD.
  • Method: AutoDock 4.2 was used with the Lamarckian genetic algorithm. The 3D structures were derived from the Protein Data Bank (PDB ID: 4PJZ for TEIC A2-2; 3CGT for native β-CD).
  • Goal: To visualize the formation of inclusion complexes and identify binding modes.

• In Vitro Protein Binding Assay:

  • Setup: Human serum was spiked with clinically relevant concentrations of SBECD (0, 100, 300, 1000 µg/mL).
  • Procedure: TEIC was added, incubated, and ultrafiltration (30 kDa) was performed to separate bound vs. unbound fractions.
  • Analysis: Unbound fractions of TEIC components were quantified to determine the effect of SBECD on protein binding.

3. Key Contributions

• Excipient-Drug Interaction Identification: This is the first study to identify SBECD, a common pharmaceutical excipient, as the specific agent responsible for reducing TEIC plasma concentrations, rather than the active drug PSCZ itself.
• Mechanistic Elucidation: The study provides a comprehensive mechanistic explanation: SBECD forms an inclusion complex with the hydrophobic side chain of TEIC, displacing it from serum proteins (specifically Human Serum Albumin).
• Differentiation of TEIC Components: The research highlights that the interaction is component-specific, significantly affecting the lipophilic A2 group of TEIC while having a lesser effect on the hydrolysis product A3-1.
• Clinical Relevance: It challenges the assumption that excipients are inert, demonstrating that SBECD-containing formulations can alter the pharmacokinetics of highly protein-bound drugs.

4. Key Results

• Clinical Findings:

  • The TEIC C/D ratio was significantly lower (approx. 35% reduction) during i.v. PSCZ administration compared to no PSCZ (Estimate: -1.24; 95% CI: -1.74 to -0.74).
  • Oral PSCZ administration showed no statistically significant effect on TEIC C/D ratios, confirming the interaction is specific to the i.v. formulation (which contains SBECD).

• Animal Pharmacokinetics:

  • Pretreatment with i.v. PSCZ or SBECD alone significantly decreased the AUC of TEIC and increased urinary excretion compared to saline controls.
  • The effect was most pronounced in the A2 group (lipophilic components), whereas the A3-1 component showed no significant change in pharmacokinetics.

• Molecular Modeling:

  • Docking simulations revealed that the hydrophobic side chain of TEIC A2-2 fits into the hydrophobic inner cavity of SBECD.
  • Two binding modes were identified (Type I and Type II), both involving the accommodation of the TEIC side chain within the cyclodextrin cavity.

• Protein Binding Assays:

  • SBECD caused a concentration-dependent increase in the unbound fraction of TEIC.
  • At 300 µg/mL SBECD, the unbound fraction increased dramatically for the A2 group (e.g., 25.9-fold for A2-4/2-5) compared to serum without SBECD. The A3-1 component showed a smaller increase (1.3-fold).

5. Significance and Implications

• Therapeutic Monitoring: Clinicians must be aware that co-administering i.v. PSCZ with TEIC can lead to subtherapeutic TEIC trough levels due to enhanced renal clearance, not metabolic inhibition. Dose adjustments or more frequent therapeutic drug monitoring (TDM) may be required.
• Excipient Safety: The study underscores that pharmaceutical excipients like SBECD are not always pharmacokinetically inert. They can form stable inclusion complexes with drugs possessing hydrophobic side chains, altering elimination pathways.
• Broader Applicability: Since SBECD is used in other injectable formulations (e.g., for telavancin and oritavancin), this interaction mechanism may apply to other lipoglycopeptides or drugs with similar hydrophobic structures.
• Future Directions: The authors recommend prospective studies to quantify the clinical impact on treatment efficacy and to investigate interactions with other SBECD-containing drugs.

In conclusion, the paper demonstrates that the reduction in TEIC plasma levels is driven by SBECD-mediated displacement of TEIC from serum proteins, leading to increased free drug fraction and subsequent renal excretion. This interaction is specific to the i.v. formulation of PSCZ and poses a significant risk for treatment failure in HSCT patients if not recognized.