# Saliva Testing: A Painless Alternative for Monitoring Medications and Precision Dosing

Therapeutic drug monitoring (TDM) traditionally requires blood draws, which can be painful and difficult for vulnerable patients. This review of 112 scientific articles examined whether saliva could serve as an alternative testing fluid, finding that 53 of 73 drugs studied (73.6%) can be reliably monitored through saliva. Researchers also developed mathematical models that use saliva drug levels to guide precise medication dosing, with promising results for antibiotics, antifungal drugs, seizure medications, and steroids. This patient-friendly article explains which drugs work with saliva testing, how the research was conducted, and what these findings could mean for the future of medication management.

# Saliva Testing: A Painless Alternative for Monitoring Medications and Precision Dosing

## Table of Contents

- Key Points
- Why This Research Matters
- How the Researchers Conducted This Review
- Key Findings: Which Drugs Can Be Monitored Through Saliva?
- Representative Research Cases
- Factors That Affect Saliva Drug Levels
- What This Means for Patients
- Study Limitations
- Recommendations for Patients and Researchers
- Frequently Asked Questions
- Source Information

## Key Points

- Of 73 drugs studied, 53 (73.6%) could be reliably monitored through saliva, while 13 were unsuitable and 7 had conflicting evidence.
- Saliva reflects free, active drug levels; mathematical models can guide precise dosing from saliva samples for antibiotics, antifungals, seizure drugs, and steroids.
- In newborns, saliva-based monitoring for amikacin and gentamicin achieved target levels in 77.6–81% of simulated patients, reducing the need for blood draws.
- Saliva collection is painless, requires no training, and can be done at home, but accuracy depends on saliva flow, timing, hydration, and mouth rinsing after liquid medications.
- Drugs with high protein binding and low permeability, called SECS Class IV, generally cannot be measured in saliva; laboratory tests must be sensitive enough for low levels.

## Why This Research Matters

When you take a medication, the level of that drug in your body determines whether it will work effectively or cause harmful side effects. **Therapeutic drug monitoring (TDM)** is the practice of measuring drug concentrations in blood or other body fluids to make sure levels stay within a "therapeutic window" — high enough to be effective, but low enough to avoid toxicity.

Think of it like tuning a guitar: too loose and it won't play correctly; too tight and the string snaps. Similarly, if a medication level is too low, it won't treat the condition; if too high, it can cause dangerous side effects.

Traditionally, TDM relies on blood samples, which must be collected by trained professionals using needles. This approach has several drawbacks:

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**Pain and anxiety** — especially for children and needle-phobic patients
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**Risk of infection** — any needle stick carries some risk
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**Potential for iatrogenic anemia** — blood loss from repeated sampling, particularly dangerous for premature babies
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**Requires trained personnel** — limiting its use in home or remote settings

Saliva offers an intriguing alternative. Because of their large molecular size, protein-bound drugs rarely enter saliva, which means salivary drug concentrations actually reflect the **free (unbound) drug** — the portion that is biologically active in the body. Saliva collection is painless, cost-effective, requires no special training, and can be done almost anywhere.

The researchers also explored **model-informed precision dosing (MIPD)**, a sophisticated approach that uses mathematical modeling and computer simulation to combine patient information (like age, weight, and organ function), drug properties, and disease characteristics to determine the exact dose each individual needs.

## How the Researchers Conducted This Review

The research team from Fujian Medical University Union Hospital in China conducted a systematic search of the PubMed database, looking for all studies on saliva-based TDM published from the database's beginning through November 2024. They used keywords including "Therapeutic Drug Monitoring," "Saliva," "Salivary," and "Oral fluid."

Studies were included only if they met strict criteria:

1. Involved human participants
1. Provided paired saliva and plasma drug concentration data
1. Were published in English

Studies were excluded if they involved animals, were review articles, were published in other languages, lacked saliva pharmacokinetic data, had no full text available, or showed no relationship between plasma and saliva concentrations.

After screening, **112 articles were included in the final review**, published between **1979 and 2023**. These studies covered **73 different drugs**.

## Key Findings: Which Drugs Can Be Monitored Through Saliva?

The results were encouraging but not universal. Not every drug appears in saliva at measurable levels.

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**53 drugs (73.6%)** — studies supported saliva as a reliable matrix for TDM
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**13 drugs (17.8%)** — studies did not support saliva-based TDM
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**7 drugs (9.6%)** — studies produced conflicting results, with some supporting and some rejecting saliva testing

Whether a drug can be monitored in saliva depends on several key properties. The researchers describe a system called the **Salivary Excretion Classification System (SECS)**, which sorts drugs into four classes:

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**Class I**: Low protein binding, high intestinal permeability — efficiently excreted into saliva
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**Class II**: Low protein binding, low intestinal permeability — also efficiently excreted into saliva
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**Class III**: High protein binding, high intestinal permeability — moderately secreted through passive diffusion, despite low free drug fractions
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**Class IV**: High protein binding and low intestinal permeability — negligible salivary concentrations due to limited passive diffusion; these drugs are generally unsuitable for saliva-based TDM

In simple terms, drugs that aren't heavily bound to blood proteins and that can pass through membranes are good candidates for saliva testing. Drugs that are tightly bound to proteins and can't cross membranes easily are not.

## Representative Research Cases

The review highlighted six representative drugs studied in detail. Here's what the researchers found for each.

### Amikacin: A Lifesaving Antibiotic for Newborns

Amikacin is an intravenous antibiotic often used to treat serious infections in premature and full-term newborns. In a study by Samb and colleagues, **23 preterm and term neonates** were studied, and researchers built a mathematical model that connected a simulated saliva compartment to a previously validated two-compartment plasma model.

Using just **1 to 5 simulated salivary concentrations**, researchers performed dose adjustments. The results were striking: **77.6% to 79.2% of simulated patients achieved the target plasma concentrations** (peak levels between 24-35 mg/L and trough levels below 5 mg/L). This outperformed the fixed-dose approach, where only **73.1%** of patients reached their targets.

The researchers noted that saliva-based TDM could be especially valuable for **preterm newborns experiencing delayed-onset sepsis** — a life-threatening condition where every blood draw carries added risk.

### Voriconazole: An Antifungal Medication

Voriconazole treats serious fungal infections. Kim and colleagues used a one-compartment model with first-order absorption and elimination to characterize the drug's behavior. They introduced a **proportionality factor of 0.501** to correlate salivary voriconazole levels with the stable plasma compartment.

This adjustment improved the model's accuracy compared to using a separate salivary compartment in isolation. The model's predictive performance was validated through visual predictive checks and simulations, offering a promising pathway for saliva-based voriconazole dosing.

### Gentamicin: Another Key Neonatal Antibiotic

A study by Samb and colleagues involved **54 neonates treated with gentamicin**. The research team used a non-linear mixed effects model (NONMEM) to build a population pharmacokinetic model, integrating salivary gentamicin concentrations into a previously published two-compartment model.

The simulations revealed that **TDM using four saliva samples achieved target attainment rates of 81%**. Interestingly, this actually outperformed plasma-based approaches in some comparisons (94% with two plasma samples; 87% with one sample). The model provided actionable insights to optimize gentamicin dosing in newborns, confirming that saliva-based TDM is a **clinically viable strategy** for this drug.

### Clonazepam: A Seizure Medication

Kruizinga and colleagues studied **20 healthy subjects** to develop a population pharmacokinetic model for clonazepam, a medication used for seizures and panic disorders. They discovered an important practical issue: when patients take an oral solution, the liquid can contaminate saliva samples during the **first four hours after dosing**, causing a non-linear relationship between saliva and plasma concentrations.

The researchers introduced a mathematical adjustment to account for this contamination. Using Bayesian maximum a posteriori optimization, they found that when only **one saliva sample** was collected, the limits of agreement (LOA) between true and predicted plasma concentrations ranged from **−28% to +36%**. When more saliva samples were collected, these limits improved to **−18% to +17%** — a much tighter and more clinically acceptable range.

The researchers recommend that patients **thoroughly rinse their mouths** after taking oral solutions to avoid this contamination problem. They also noted that regular tablets might avoid this issue, but the oral solution was studied because the target population includes children.

### Busulfan: A Chemotherapy Drug Requiring Precise Dosing

Busulfan is a powerful chemotherapy drug used before bone marrow transplantation, where precise dosing is critical — too little means the transplant may fail; too much means severe toxicity. Xu and colleagues studied **66 patients with hematological malignancies** (blood cancers).

Their population pharmacokinetic model used a one-compartment model with constant-rate infusion. They compared two approaches for incorporating salivary concentrations and determined that a **proportionality factor within the plasma compartment was superior** to creating a separate saliva compartment.

The Monte Carlo simulation results were impressive: a root mean square percentage error (a measure of prediction accuracy) as low as **13.74%**, with 95% limits of agreement ranging from **−23.40% to +31.92%** using just a single trough saliva sample. This means the model is clinically applicable for individualizing busulfan dosing based on salivary drug concentration.

### Prednisolone: A Steroid With a Surprising Finding

Prednisolone is an active steroid medication, and its inactive precursor is prednisone. Once taken, prednisone converts to prednisolone in the body. Nynke Teeninga and colleagues studied **19 healthy volunteers** to understand this metabolic relationship.

The key finding was a **strong correlation (r = 0.931, P < .01)** between salivary prednisolone and free serum prednisolone concentrations. In contrast, the correlation between salivary prednisone and serum prednisone was weak **(r = 0.318, P < .01)**.

This is statistically highly significant — the P value of less than 0.01 means there is less than a 1% chance this finding occurred by random chance. The clinical takeaway: saliva-based monitoring of prednisolone is a reliable stand-in for systemic free drug levels, offering a non-invasive alternative for patients who need long-term steroid monitoring.

## Factors That Affect Saliva Drug Levels

The review identified many factors that influence whether — and how much — a drug appears in saliva. This isn't a simple process, and these factors can affect accuracy.

### Does the Patient Produce Enough Saliva?

Saliva comes from three pairs of major glands: the **parotid, submandibular, and sublingual glands**. Many things affect saliva production:

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**Circadian rhythm**: Saliva flow peaks in the afternoon and varies throughout the day
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**Body position**: Flow increases when standing and decreases when lying down
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**Hydration**: More water intake increases saliva; dehydration decreases it
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**Food and drink**: Acidic foods and carbonated beverages stimulate saliva production
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**Emotions**: Anxiety, nervousness, anger, and excitement may change saliva production, though studies are limited

Many common medications also reduce saliva, including:

- Pain relievers (analgesics) and appetite suppressants
- Antirheumatic drugs and anticholinergics
- Antidiarrheal and antiemetic medications
- Antihistamines (allergy medications) and antihypertensives (blood pressure medications)
- Diuretics (water pills) and medications for Parkinson's disease
- Anti-anxiety medications, antidepressants, and antipsychotic medications

Certain diseases also reduce saliva production, including **congenital dry mouth or dry mouth syndrome**, chronic rheumatoid arthritis, graft-versus-host disease after bone marrow transplantation, systemic lupus erythematosus, alcoholic cirrhosis of the liver, cystic fibrosis, Addison's disease, Cushing's syndrome, primary aldosteronism, and radiation therapy for head and neck cancers. Age and gender can play a role too — salivary flow tends to be higher in men than women, though studies on age effects have produced conflicting results.

### The Saliva-to-Plasma (S/P) Ratio

To use saliva for TDM, there must be a predictable relationship between drug concentrations in saliva and those in plasma (blood). This relationship is called the **saliva/plasma (S/P) ratio**, and it varies between drugs.

Several factors affect the S/P ratio:

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**Molecular weight**: Large drug molecules have difficulty entering saliva, except in unusual situations like breaks in the oral mucosa
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**Lipid solubility**: Drugs that dissolve well in fats are more likely to enter saliva through free diffusion — this is the main factor controlling drug movement from blood to saliva
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**Drug ionization (pKa)**: Only non-ionized (uncharged) drug molecules can cross cell membranes. The drug's pKa and the pH of saliva both matter. For basic drugs, a higher pKa means more ionization and less entry into saliva; the opposite is true for acidic drugs
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**pH differences**: Normal plasma pH is 7.35-7.45, while saliva pH ranges from 5.8 to 7.8. Because plasma is more basic than saliva, acidic drugs typically have S/P ratios of ≤1, while basic drugs typically have S/P ratios of ≥1
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**Protein binding**: Drug molecules attached to plasma proteins can't pass through capillary walls, so drugs with high protein binding have difficulty entering saliva

There's also an important phenomenon related to **arteriovenous differences**. During drug absorption, the drug concentration in arterial blood is higher than in venous blood. During elimination, this can reverse. Salivary glands have abundant blood flow, so these fluctuations must be considered when comparing saliva concentrations with blood drawn from a vein in the arm.

Different elimination kinetics in plasma versus saliva can also make the S/P ratio unstable. Finally, when a drug's S/P ratio shows high variability, saliva becomes a more difficult TDM matrix to use reliably.

### Assay Sensitivity Is Essential

Drug concentrations in saliva are usually lower than those in plasma. This means **highly sensitive laboratory tests are a prerequisite** — the drug concentration must reach the lowest detection limit of the assay before TDM can be performed. If the test isn't sensitive enough, saliva TDM simply won't work reliably.

## What This Means for Patients

This research could meaningfully change how certain medications are monitored. Here's what it means in practical terms:

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**Less pain for newborns**: Premature and full-term infants often need antibiotics like amikacin and gentamicin. Saliva-based monitoring could significantly reduce the number of blood draws these fragile patients endure, lowering the risk of anemia and infection.
-
**Better care for needle-phobic patients**: Children who fear needles, individuals with intellectual disabilities, and immunocompromised patients could all benefit from a painless monitoring option.
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**Home-based monitoring**: Since family members can collect saliva samples without special training, patients could potentially have samples collected at home and mailed to a laboratory, reducing hospital visits.
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**More accurate measurement of active drug**: Because saliva reflects free (unbound) drug concentrations rather than total drug (bound plus unbound), saliva TDM may actually provide a more accurate picture of the drug that's working in the body.
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**Smarter dosing with mathematical models**: The population pharmacokinetic models described in this review can predict plasma drug levels from saliva measurements, enabling doctors to adjust doses with fewer data points.

## Study Limitations

It's important to understand what this research doesn't prove.

First, **not all drugs can be monitored through saliva**. Thirteen of the 73 drugs studied (17.8%) were not suitable, and 7 more produced conflicting results. Drugs with high protein binding and low permeability (SECS Class IV) are generally unsuitable.

Second, **patient-specific factors complicate saliva testing**. Saliva production varies with age, gender, medications, diseases, hydration status, time of day, body position, and even emotions. A patient with dry mouth from another medication may not produce enough saliva for testing.

Third, **the S/P ratio isn't always constant**. For drugs like clonazepam, the oral solution itself contaminated saliva samples. Arteriovenous differences, nonlinear elimination kinetics, and concentration-dependent protein binding can all make saliva levels unpredictable.

Fourth, **saliva-based PopPK modeling is still in its infancy**. The review notes that population pharmacokinetic modeling based on saliva TDM for precise drug delivery has only been initially attempted for a few drugs, and the application **has yet to be verified in large clinical studies**. Most current saliva TDM research has been conducted abroad, with limited research in China.

Finally, **sensitivity of laboratory assays** is a practical barrier. Saliva drug concentrations are often lower than plasma concentrations, requiring more sensitive — and potentially more expensive — laboratory equipment.

## Recommendations for Patients and Researchers

For patients currently undergoing therapeutic drug monitoring, it's worth asking your physician or pharmacist whether saliva-based testing might be an option for your specific medication. While saliva TDM isn't yet widely available in clinical practice, the evidence supporting it for drugs like amikacin, gentamicin, voriconazole, busulfan, and prednisolone is substantial.

For patients participating in saliva TDM studies or future clinical use, the research suggests these practical tips:

1.
**Rinse your mouth thoroughly** after taking oral medications, especially liquid formulations, to avoid contamination of saliva samples
1.
**Be consistent with collection timing**, since salivary flow varies by time of day, with peaks typically in the afternoon
1.
**Stay well-hydrated**, as dehydration reduces saliva flow and could affect sample adequacy
1.
**Disclose all medications you take**, including over-the-counter drugs, since many common medications reduce saliva production
1.
**Follow instructions about body position**, since lying down versus standing can alter saliva flow rates

For researchers, the authors recommend continued development of saliva-based PopPK models for additional drugs, standardized methods for correlating saliva and plasma concentrations, and large-scale clinical trials to verify that saliva-guided dosing achieves outcomes comparable to traditional blood-based TDM.

## Frequently Asked Questions

### What is therapeutic drug monitoring and why is it done?

Therapeutic drug monitoring measures drug levels in your body to keep them in a safe, effective range. Levels that are too low may not treat your condition; levels that are too high can cause dangerous side effects. Traditionally it uses blood samples, but saliva may offer a painless alternative for some medications.

### How does saliva drug testing compare to blood testing for accuracy?

Saliva reflects the free, active drug in your body, while blood measures total drug. Mathematical models can predict blood levels from saliva samples. For example, one study achieved target gentamicin levels in 81% of newborns using four saliva samples. Accuracy depends on the drug and collection method.

### What factors can affect saliva drug levels and test accuracy?

Saliva production varies with time of day, body position, hydration, food, emotions, age, and gender. Many medications and diseases reduce saliva flow. Drug properties like protein binding and pH also affect saliva levels. Rinsing your mouth and staying hydrated can improve accuracy.

### Is saliva testing painful and can I do it at home?

Yes, saliva collection is painless and requires no special training, so samples can be collected at home and mailed to a lab. This is especially helpful for newborns, needle-phobic patients, and those who need frequent monitoring. However, not all drugs can be measured this way yet.

### What should I do if I'm having saliva drug level testing?

Rinse your mouth thoroughly after taking oral medications, especially liquids, to avoid contaminating the sample. Collect samples at the same time each day, stay well-hydrated, tell your doctor about all medications you take, and follow instructions about body position, since lying down can affect saliva flow.

### Are there risks or limitations to saliva drug monitoring?

Saliva testing is not suitable for all drugs, especially those that are highly protein-bound. Laboratory assays must be sensitive enough to detect low saliva drug concentrations. Patient factors like dry mouth can affect sample adequacy. Large clinical studies are still needed before widespread use.

### When should I seek a second opinion about using saliva testing instead of blood draws for monitoring my medication?

Saliva testing is a painless option for monitoring many medications, but it doesn't work for every drug. Among 73 drugs studied, 53 (73.6%) were reliably measurable in saliva, while 13 were not and 7 gave conflicting results. Drugs that are highly protein-bound and poorly permeable generally cannot be monitored this way. If your medication is being monitored with frequent blood draws, a second opinion could clarify whether saliva-based monitoring is a viable, evidence-backed alternative for your specific drug. Diagnostic Detectives Network provides independent expert second opinions on medication monitoring options.

## Source Information

**Original article title:** Saliva as a TDM Matrix and Its Application in the Model-Informed Precision Dosing.

**Authors:** Xu B, Wen Y, Lu J, Liu M, Luo X, Huang W, Xie H, Cheng Y, Qiu H, Wu X.

**Journal:** The Journal of Clinical Pharmacology, 2025, Volume 65, Issue 12, Pages 1650–1660

**Publication details:** Published by Wiley Periodicals LLC on behalf of the American College of Clinical Pharmacology. DOI: 10.1002/jcph.70083

**Corresponding author:** Xuemei Wu, PhD, Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, China

This patient-friendly article is based on peer-reviewed research. The original study was submitted on February 24, 2025, and accepted on June 29, 2025.

*Note: This article is provided for educational purposes only and is not a substitute for professional medical advice. Always discuss medication monitoring options with your healthcare provider.*


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