Model-Informed Precision Dosing for Conditioning Regimens: Busulfan, Fludarabine, ATG, and More

What Does a "Personalized Conditioning Regimen" Really Mean?

For patients with blood cancers and disorders—like chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin’s lymphoma, or myelodysplastic syndrome—a hematopoietic stem cell transplant (HCT) can be life-saving, and sometimes even curative. In recent years, innovative treatments such as CAR T-cell therapy and gene therapy have also expanded curative options. But before patients can receive these therapies, they go through a conditioning regimen—a carefully designed set of chemotherapy agents that prepare the body for the treatment to come.

Getting the dose of these conditioning drugs right is critical. Agents like busulfan, fludarabine, and anti-thymocyte globulin (ATG) can mean the difference between a successful transplant and serious complications. Too much exposure increases toxicity and risk of graft-vs-host disease (GvHD). Too little exposure, and patients face relapse or graft failure.

That’s where model-informed precision dosing (MIPD) comes in. Unlike the old approach of dosing strictly by body weight or body surface area (methods that often miss the mark because of patient-to-patient variability) MIPD uses pharmacokinetic models and patient-specific data to deliver a dose that’s truly individualized.

• Model-based dosing means using validated PK models that factor in patient characteristics (like weight or absolute lymphocyte count in the case of ATG) to calculate the starting dose.
• PK-guided dosing involves taking blood samples, measuring actual drug concentrations in the body, and then adjusting doses based on exposure metrics like area under the curve (AUC).

Together, these approaches move us toward a more precise, patient-centered way of delivering conditioning regimens—giving patients the best chance at cure while reducing risks along the way.

Why MIPD Matters in Conditioning Therapy

Many centers still calculate drug exposure (AUC) using noncompartmental analysis (NCA). While reliable, NCA requires intensive blood sampling and assumes first-order exponential decay, which doesn’t always reflect real-world patient variability.

Model-informed precision dosing (MIPD) improves on this by combining model-based initial dosing with Bayesian forecasting for PK-guided adjustments. Studies show it delivers more precise and accurate AUC predictions, and guidelines now encourage its use.

Beyond accuracy, MIPD is also more practical. Integrated into the electronic health record, it reduces the number of blood samples needed and allows smoother regimens — such as once-daily busulfan dosing instead of four times a day. The result: better precision with less burden for patients and providers.

Busulfan: Model-Based Dosing and Real-World Evidence

Among conditioning agents, busulfan has the strongest track record with MIPD. Over the last decade, researchers have developed a growing library of validated population PK models, many of which are now embedded directly into MIPD software. These models cover diverse patient populations, and some even focus on specific groups—for example, Takahashi et al. created a model tailored to patients with inherited metabolic disorders.

But how many models do we really need? A study by Mahomedradja et al. compared several validated busulfan PK models to see if they could be used without blood draws. The verdict: blood sampling still adds value, but the bigger message was that the field should focus on starting to implement the models into practice rather than focusing on creating new ones.

Fludarabine: Renal Clearance and Smarter Dosing

For fludarabine, MIPD relies on model-based dosing without the need to take therapeutic drug monitoring blood samples (TDMs), making it easier to implement in practice. Because the drug is cleared through the kidneys, incorporating renal biomarkers into dosing models helps clinicians more accurately reach target exposures tied to better outcomes. Compared to conventional weight-based dosing, this approach increases the likelihood of patients achieving exposure ranges, with better exposure linked to improved survival and reduced relapse.

ATG: ALC-Based Dosing for Greater Precision

With ATG, the key is its interaction with lymphocytes. By using absolute lymphocyte count (ALC) alongside body weight, models can better individualize dosing, reducing the risk of over- or under-treatment. Without MIPD, patients are more likely to experience graft failure or graft-vs-host disease due to under- or overexposure, but model-based dosing helps strike the right balance for safer, more effective therapy.

Together, fludarabine and ATG are examples that show how MIPD brings practical, exposure-driven dosing strategies beyond busulfan.

Can Other Conditioning Agents Benefit from MIPD?

Absolutely. While busulfan, fludarabine, and ATG have the most data, other conditioning agents are now under investigation for MIPD.

• Melphalan: PK models exist, but poor drug stability in samples has slowed adoption.
• Clofarabine: Less common, but early work suggests model-based dosing could mirror the benefits seen with fludarabine.
• Treosulfan: Once thought to need little PK monitoring, new evidence linking exposure (AUC) to mortality shows MIPD may be critical here.
• Thiotepa: Both thiotepa and its metabolite TEPA have been modeled, hinting at future applications for precision dosing.

As research grows, these agents may join busulfan, fludarabine, and ATG in demonstrating how MIPD can refine conditioning regimens across the board.

Pharmacist-Led MIPD: A New Standard in Conditioning

The future of MIPD in conditioning regimens is moving toward comprehensive platforms that extend beyond busulfan, fludarabine, and ATG to encompass full regimen-level optimization. Advances in real-time analytics, automated sampling strategies, and integration of pharmacogenomics will likely allow for even greater personalization of therapy.

The ultimate goal is a conditioning strategy tailored to each patient’s biology to maximize safety, efficacy, and survival outcomes. MIPD plays a critical role in achieving this. Rooted in pharmacokinetic principles and individualized dosing, MIPD is well-aligned with the expertise of clinical pharmacists and specialists. Positioned at the intersection of PK science, direct patient care, and medication management, they are essential to translating MIPD into actionable, bedside decisions. By adopting MIPD, pharmacists can optimize therapy with greater confidence, standardize best practices across institutions, and elevate the standard of care in transplant and cellular therapy.

Conclusion: Advancing Conditioning with MIPD

Bayesian MIPD has reshaped model-based and PK-guided dosing in transplant and cellular therapy, consistently improving target attainment and clinical outcomes across high-risk conditioning agents. The field is evolving toward fully individualized, model-informed therapy that moves beyond traditional weight- or BSA-based dosing and conventional therapeutic drug monitoring.

Interested in implementing MIPD for transplant and cellular therapy? Learn more about our BMT conditioning agent modules below:

Appendix: Summary of Key Clinical Studies

Take a look at recent articles published on TDM and MIPD for various conditioning agents below.

Busulfan

Fludarabine