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Correspondence to Author: Regrid Weiter, 

Swiss Eye Institute, Berner Augenklinik am Lindenhofspital, Bremgartenstrasse 119, CH‑3012 Bern, Switzerland.

Abstract:

Context:   Empirical guidelines, mostly grounded in experimental data, are utilized to treat pregnancy-acquired toxoplasmosis. Our study aims to close this gap in the literature by providing pharmacological data on pregnant women treated with pyrimethamine (PY) and sulfadiazine (SA) for acute Toxoplasma gondii infection.
Techniques:   89 pregnant women with primary Toxoplasma infection (PT) who were treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10–15 mg per week) were included in this retrospective case–control study. These were contrasted with a group of 17 women who had been treated for acute ocular toxoplasmosis (OT) with a 75 mg PY dose at first, followed by a 25 mg dose twice daily, while adhering to the same SA and folinic acid regimen. There was no documentation of the precise time between drug administration, blood work, and co-medication. Using liquid chromatography–mass spectrometry, the plasma levels of PY and SA were measured 14±4 days following treatment initiation. The Mann–Whitney U test was used to compare the results at a p0.05 level.
Results:   SA levels were less than 20 mg/l in 23 PT patients (26%). Out of the 23 patients, 15 of them (17%) had PY levels that were lower than 700 µg/l. Despite the same SA dosage method, there were notable differences in the drug concentrations between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p=0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p=0.015).
Conclusion:   When compared to OT patients, pregnant women with PT had median SA plasma concentrations that were 34% lower, and in a significant number of PT patients, these concentrations were below a lower reference value of 50 mg/l. Thus, a still-unsupportable transmission risk may be explained by the interindividual variability of plasma concentrations combined with consistently reduced medication levels and potentially decreased compliance in pregnant women. It is worthwhile to take into account systematic drug-level testing in PT receiving PY/SA treatment.

Keywords:   Primary toxoplasmosis, Ocular toxoplasmosis, Pyrimethamine, Sulfadiazine, Plasma concentration, Liquid chromatography–mass spectrometry.

Introduction:  When a mother contracts Toxoplasma gondii while she is pregnant, the infection may spread to the developing baby. Congenital Toxoplasma infections in children can cause severe clinical signs such hydrocephalus, retinochoroiditis, or cerebral calculi, or they might be entirely asymptomatic (with subclinical infection). Later in life, the parasite can reactivate in children with subclinical infection and cause retinochoroiditis, often known as ocular toxoplasmosis (OT). Early treatment of newly infected pregnant women is justified to lower the risk of transmission and congenital toxoplasmosis [1–5]. The combination of pyrimethamine (PY) and sulfadiazine (SA) is thought to be the most effective since the two medications work in concert, cross the placenta, and build up in the tissues of the mother and the fetus. Studies using observational data have shown a link between prenatal care and the avoidance of symptomatic illness in newborns [6].
It is still unclear if treatment failures in human congenital toxoplasmosis are caused by inadequate medication concentrations in the fetal tissue or by treatment starting later than planned following maternal infection [16]. Studies conducted in vitro have shown that the medications function in a concentration-dependent manner. When combined, mice’s plasma concentrations for PY and SA should be at least 100 µg/l and 25 mg/l, respectively [17]. Maximum concentrations of 220 µg/l for PY and 58.7 mg/l for SA were achieved in rhesus monkeys using a medication regimen that was also used on people [13]. Therapeutic medication monitoring in patients with Toxoplasma infection has shown that plasma concentrations are not only variable among individuals and different patient groups, but also unpredictable. even with conventional treatment [2, 18–21]. Thus far, it can be presumed that plasma concentrations in the range of 700– 1300 µg/l (PY) and 50–150 mg/l (SA) are effective in humans [14, 22]. It is necessary to give folinic acid concurrently to avoid bone marrow suppression, a hazardous side effect of PY. There are data on the pharmacokinetics of PY and SA mostly for children with congenital toxoplasmosis [2, 18, 19, 21, 23] and males who are HIV-positive [15]. However, pharmacological information from expectant patients receiving PY and SA for an acute Toxoplasma infection is currently lacking [18]. A pharmacological explanation for the combined treatment’s unsatisfactory efficacy in preventing vertical transmission is still warranted. We reasoned that comparing the plasma concentrations of PY and SA in OT-affected women and pregnant women with pregnancy-acquired toxoplasmosis would shed light on the potential contributions of pregnancy-associated pharmacological variables. Our case-control study sought to determine potential differences in PY and SA plasma concentrations between pregnant and non-pregnant women based on similar patient characteristics and a comparable treatment strategy.
In order to measure the plasma concentrations of PY and SA, blood or plasma samples were drawn about 14 days following the start of the treatment and sent to the Southern German reference laboratory (Laboratory Harold Hlobil, Sindelfngen, Germany). For comparison, serum samples from 17 HIV-negative women with comparable ages (17–35, mean 26.1±5.3 [23.6; 28.5] years) who received treatment for acute symptomatic Toxoplasma retinochoroiditis at the University Hospital Bern (Inselspital) between 1992 and 2001 were available. (Tables 1 and 2). The OT patients received the same SA dosage as the PT group for a minimum of six weeks, but their treatment began with a loading dose of 75 mg PY, followed by 25 mg PY given twice daily. Every person had blood samples taken for side effect control on a regular basis, usually 14 days (range 11–17 days) after treatment started. The leftover samples were kept in a biobank at -18 °C until their analysis in 2011. In order to confirm the stability of PY and SA in plasma during long-term storage at −18 °C, we also included samples from ten male HIV-negative patients who were treated for acute OT during the same period and who underwent the identical methods for sampling, storage, and analysis. Table 2 presents the group’s baseline characteristics. Because the treatment procedure had shifted from PY/SA to the more recent standard, there were no more recent blood samples from patients treated after 2001. 2001 saw the introduction of the Fansidar® fx combination, which was pyrimethamine and sulfadoxine; by 2004, it had changed to a fixed-dose combination of trimethrim 160 mg and sulfamethoxazole 800 mg twice a day. Since each patient was an outpatient, precise timing of medicine administration and blood sample collection was unknown. Consequently, figuring out specific trough-to-peak ratios was not feasible.

Outcomes:   The two groups’ initial features are shown. within Table 1.We observed no difference in plasma concentrations by grouping OT samples based on when they were sampled (Group 1: 10– 12 days, Group 2: 13–15 days, and Group 3: 16–18 days after treatment initiation). This indicates that by the time blood was sampled, both PY and SA concentrations had already reached a steady-state (Fig. 1a, b).The OT group’s steady-state findings led us to believe that the PT group would likewise reach its PY and SA steady-state plasma concentrations following this period. The PY levels (Fig. 2a) were found to be 34% higher in women with OT (1230 [780; 1890] µg/l) compared to those in pregnant women with PT (810 [745; 917] µg/l; p=0.006), which is consistent with the difference in dosing (50 mg/ day vs. 25 mg/day). This was determined by comparing the median values of both drugs for both groups. Even though both groups used the same SA dosage regimen, the SA levels differed by 34% (PT 46.2 [39.9; 54.4] mg/l vs. OT 70.4 [52.4; 89] mg/l; p=0.015).
The majority of PT patients were, by the reference values, underdosed for SA if we assume, based on published research, an upper concentration limit for PY of 1700 µg/l and a lower concentration limit for SA of 50 mg/l. In contrast, PY concentrations were above the desired value in the majority of OT samples (Fig. 2b). SA levels fell below 20 mg/l in 23 of the 89 PT patients (26%) that were evaluated. Parallel to this, 15 of these 23 individuals (17% of total patients) had PY levels below the desired 700 µg/l concentration.
Similar values for both medications were found when the serum concentrations of male and female patients with acute OT receiving PY and SA treatment were compared (Table 2). Since the concentrations for males after the immediate workup of unfrozen plasma samples are in good agreement with published pharmacokinetic results [23, 24], the observed differences in the plasma concentrations of either drug cannot be explained by the different storage conditions for PT and OT samples
Concentrations of 50–150 mg/l of SA are thought to be therapeutic for the majority of infections [22]. However, in 26% of our PT patients, the concentration of SA was less than 20 mg/l, and in 17% of the patients, the concentrations of both PY and SA were not reached. This is quite consistent with the 5-to 13% clinically documented transmission rates in Europe [3, 25]. Pregnant individuals had reduced medication levels even with the same SA treatment plan. The median SA plasma concentration in PT patients was more than 34% (46.2 vs. 70.4 mg/l) lower than that in the OT group when compared to those in non-pregnant women with OT, suggesting that the treatment procedure itself is not insufficient.
The interpretation of results for a single patient is limited by the consequent absence of more specific information regarding body size, weight, general health, comorbidities, and their influence in pregnant patients; however, we believe that the tendency in the large patient group of pregnant women is robust. The clinical data of the second group of OT patients, whose sample size was noticeably smaller, revealed an age range that is reasonably comparable to that of the pregnant women. Significant comorbidities or equivalent treatments were absent from all of these patients, and no underlying hepatic or renal illness was found to be present.
A modification in the treatment regimen for OT after 2001 made it impossible to increase the sample size of the second group, as previously mentioned. The plasma concentrations were ascertained using blood samples obtained roughly 14 days into the treatment. This assumption was based on the subgroup analysis of non-pregnant (OT) women, which suggested that both medications would have achieved a steady state by then (Fig. 1a, b). Our study is one of the few in this field of research, despite the fact that pregnant women are typically disqualified from pharmacokinetic studies because of ethical issues. The majority of the time, anti-parasitic medication dosage during pregnancy has been empirical, with the noteworthy exception of a recent study on antimalarial medication in African women. While receiving Fansidar® care,Although the pharmacological behaviors of the two medications differ, there was an overall three-fold greater clearance for sulfadoxine in pregnant women compared to postpartum women [31–33]. This finding is consistent with our results for SA.

Conclusion:   According to our data, every sixth patient with pregnancyacquired toxoplasmosis had insufficient drug levels for both drugs. This finding could only be partially explained by missing data regarding co-medication and pregnancyassociated pharmacologic changes, as well as the time lapse between drug intake and blood sampling not being recorded. Pregnant patients’ median PY and SA concentrations were found to be 34% lower than those of non-pregnant patients receiving treatment for active OT. We need to establish how these concentrations may be explained and to what extent the observed lowerend ranges of plasma levels for PY and SA in pregnant women can be explained, given the lengthy debate around the effectiveness of prenatal Toxoplasma therapy with relation to clinical outcomes in neonates.
Future research may find that the efficacy of the medications in the foetus and infant is influenced by the presence of women and a plasma concentration in the foetus that is one-third of the mother level [35]. In order to objectively monitor compliance and other relevant parameters before implementing a treatment plan, it is crucial to measure plasma medication concentrations systematically [37]. When applied prospectively, these could be able to reduce the discrepancy between the predicted and actual results of pregnancy in human PT.

Citation:

Regrid Weiter. Sulfadiazine plasma concentrations under pyrimethamine and sulfadiazine therapy in pregnant women with acquired vs ocular toxoplasmosis: a case-control study. The Journal of Hepatology 2024.